Denosumab: A potential new treatment option for recurrent Aneurysmal Bone Cyst of the spine

ABCs are expansile osteolytic lesions typically containing blood-filled spaces separated by fibrous septae. Standard treatment includes surgical resection or curettage and packing; however, for some spinal lesions, the standard approach is not optimal. One therapeutic strategy is to treat spinal ABC with an agent that targets a pathway that is dysregulated in a disease with similar pathophysiology. Denosumab, a human monoclonal antibody to RANKL is effective in the treatment of GCT's. Spinal ABCs are a therapeutic challenge and local recurrence is a concern. We report a case of aggressive recurrent ABC of dorsal spine in a 14-year old female with progressive neurologic deficit who underwent surgical excision and decompression with a recurrence in a short period for which a decompression and fixation was done. She had a recurrence after an asymptomatic period of 6 months and neurologic worsening. Having ruled out use of embolization and radiotherapy, a remission was achieved by treatment with Denosumab using the regimen for GCTs for a duration of 6 months. Follow-up MRI and CT scans at 24 months following inception of Denosumab depicted complete resolution and no recurrence. We conclude that Denosumab can result in symptomatic and radiological improvement in the recurrent locally aggressive ABC and may be useful in selected cases. Long-term results are mandatory to confirm the efficacy of Denosumab and to evaluate local recurrence after stopping Denosumab.


Introduction
ABCs are expansile lesions accounting for approximately 15% of all primary spinal tumours [1][2][3]. Multiple treatment modalities like intra-lesional excision, Selective Arterial Embolisation, injection with sclerosing-agents and radiation have been attempted with variable improvement and recurrence rates. However, these approaches may be associated with severe morbidities, where lesion is in the thoracic spine [4,5].
Case report A 14-year-old female presented with unsteady gait and back-pain. She had undergone two previous spinal surgeries in the recent past at another hospital. The previous medical-records showed that the girl developed insidious-onset, progressive spastic sensory-motor paraparesis. MRI of the dorsal-spine ( Figure 1) suggested an intensely enhancing cystic-haemorrhagic septate expansile lesion (5.7 Â 3.1 cm) involving D5 vertebra with epidural extension (D4-D5) causing marked spinal-cord compression and oedema. The lesion was hypo-hyperintense on T2WI, with intense heterogeneous enhancement. T1 hyperintense signals suggested haemorrhagic component. SAE was ruled out by the interventional neuroradiologist due to potential risk of vascular insult to the spinal-cord. An intra-lesional excision was done and D4-D6 unilateral pedicle screw-rod fixation was performed. After 2 days of initial neurological improvement, the patient developed neurological worsening, which was attributed to a compressive surgical mass. Following re-exploration and removal (Figure 2), the patient had recovery for a period of 2 months, but again worsened neurologically. MRI revealed an increase in the epidural mass with spinal cord-compression. The patient presented to the authors at this stage. A revision decompression was performed and circumferential reconstruction was done with a mesh-cage and bilateral pedicle-screwrod fixation from D1 to D8. She made a significant neurologic recovery ( Figure 3). Histopathology revealed an ABC ( Figure 4). After 3 months, the patient had recurrent symptoms again in the form of back-pain and unsteadiness of gait that was explained by an epidural lesion (3.4 Â 2.5 cm) compressing the spinal cord with myelomalactic changes ( Figure 5). The situation had a significant negative psychological impact on the young girl. Alternative treatment options were sought and finally treatment with Denosumab was offered to the patient after thorough counselling regarding the expected benefits, experimental nature and possible adverse-effects.
She improved within a month's time. MRI at 2 months of therapy documented significant resolution of epidural compressive mass and MRI at 6 months depicted complete resolution ( Figure 6). Denosumab treatment was discontinued at 6 months and scans at 1 and 2 years showed no recurrence. CT at 2 years showed ossification of the lesion with remodelling of the spinal canal and incorporation of the mesh-cage ( Figure 7).

Discussion
ABCs are generally rare tumorous lesions of the spine, but can lead to devastating symptoms as they are capable of destructive growth. Common treatment options for ABCs include surgical resection, curettage and filling, selective arterial embolisation, total arterial embolisation or radiotherapy. For spinal ABCs, however, some of these options entail considerable risks. Sclerosant therapy was not considered in our patient as the cortices were eroded following previous     surgical excisions, and hence there was a risk of seepage of sclerosant into neuro-vascular elements leading to catastrophic complications [13]. Denosumab, a human monoclonal-antibody, binds to a cytokine receptor activator of nuclear factor-kappa Bligand (RANKL) and prevents the action of agonists acting through RANKL-receptors. This prevents the subsequent activation and proliferation of the osteoclasts [14]. Seven patients have been successfully treated with Denosumab in addition to our patient [6,[13][14][15]17] (Table 1). Clinical trials have shown that Denosumab is effective in reducing tumour mass in case of refractory, recurrent or inoperable GCT [9,10]. Denosumab also inhibits normal bone remodelling and an important toxicity of Denosumab is osteonecrosis of the jaw [18][19][20]. Again, osteopetrosis or osteosclerosis after use of Denosumab in young patients is possible [21][22][23].
Denosumab has beneficial effects as in case of recurrent ABC described in this report. Surgical endeavours had failed twice and other proven modalities were ruled out. Previous failed surgeries had left the surgeons as well as the patient and relatives in despair with low hopes of further surgeries and in the outlook for newer horizons. We were unable to find a similar report of an aggressive refractory ABC of the dorsal spine in which deployment of Denosumab was successful.   Arnaud Dubory et al. [15] Ghermandi et al. [14] Ghermandi et al. [14] Note: ABC indicates aneurysmal bone cyst; SAE, Selective Arterial Embolisation; NA, not applicable; CT, computed tomographic; MRI, magnetic resonance image; sc, sub-cutaneous.

Conclusion
We conclude that the usage of Denosumab, although based on anecdotal experiences, may be an excellent option in cases not amenable to surgical interventions and frequent recurrences. Long-term results should confirm these preliminary outcomes to standardise the treatment-guidelines.

Conflict of interest
There is no conflict of interest among the authors or the institution regarding the manuscript, the scientific work or data collection. The legal regulatory status of the device(s)/drug(s) that is/are the subject of this manuscript is not applicable in our country. No funds were received in support of this work. No benefits in any form have been or will be received from a commercial party related directly or indirectly to the subject of this manuscript. There was no breach of ethical issues by any of the authors mentioned. The manuscript has been read and approved by the authors and each one of the authors treat their work trust worthy within all ethical parameters.