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Abstract

Background: Denosumab effectively treats RANKL-mediated bone disorders by inhibiting osteoclast activity. While approved for giant cell tumours, its role in aneurysmal bone cysts (ABC) remains unclear. This review explores denosumab’s application in ABCs, focusing on its role, outcomes, and adverse effects. Methods: A scoping review adhering to PRISMA Extension for Scoping Reviews guidelines was conducted. The search involved five databases from inception until 31 December 2023. Results: From an initial 390 studies, 29 were selected post-screening involving 67 patients. The most common ABC sites were the spine (n = 42) and pelvis (n = 7). Denosumab served as primary treatment in 25 patients (37.3%), neoadjuvant in 11 (16.4%), second-line therapies after inadequate initial therapies in 24 (35.8%), and adjunct therapy in seven cases. All patients demonstrated favourable clinical and radiological responses post-denosumab. 10 patients (15%) experienced tumour recurrences: six after denosumab discontinuation (3-17 months post-cessation), three post-surgery following neoadjuvant denosumab, and one during ongoing treatment. Adverse effects reported were hypocalcaemia (n = 10), hypercalcemia (n = 14), and sclerotic metaphyseal bands (n = 2), all in the paediatric age group. While hypocalcaemia surfaced early in denosumab therapy, hypercalcaemia manifested 2.5-6 months post-discontinuation, mainly managed with bisphosphonates. Fewer than half of the studies had follow-ups that exceeded 2 years. Conclusion: Denosumab may be an effective therapy for ABC, especially for high-risk cases like spinal and pelvic tumours. It can also be utilized as a second-line for recurrence/failed initial intervention or as neoadjuvant therapy. Concerns exist about tumour recurrence and rebound hypercalcemia, necessitating careful monitoring, longer follow-up, and prophylactic measures. Prospective clinical trials are warranted for deeper insights.

Keywords

aneurysmal bone cysts denosumab recurrence hypocalcaemia hypercalcaemia

Introduction

Aneurysmal bone cysts (ABC) are benign yet locally aggressive bone tumours first described in 1942 by Jaffe and Lichtenstein¹ with potential for local recurrence.² They are relatively rare tumours, representing 1%-2% of primary bone and 15% of primary spine tumours. ABC can involve any skeletal site but most commonly manifests within the metaphysis of long bones and the spine.^2,3 These tumours commonly develop during the first two decades of life,^2,4 presenting as swelling, pain, and pathologic fractures. When located in the spine, they can lead to neurologic deficits by compressing the nerve roots or spinal cord.^3,5 In approximately 70% of cases, ABCs may manifest as primary tumours. In comparison, in 30% of cases, they appear as secondary tumours in conjunction with conditions such as osteoblastoma, giant cell tumour of bone (GCTB), chondroblastoma, telangiectatic osteosarcoma, fibrous dysplasia, and non-ossifying fibromas.^2–4

ABC are osteolytic tumours, blood-filled cavities separated by fibrous septate.^2,4 The cellular component of ABC comprises osteoclast-like giant cells expressing receptor activators of nuclear factor kappa B (RANK) and neoplastic stromal cells expressing RANK ligand (RANKL).³ On a molecular level, 65%-70% of primary ABC demonstrate translocation t (16;17) (q22; p13). This translocation results in the fusion of the promoter region of the osteoblast cadherin 11 gene (CDH11) on chromosome 16q22 with the ubiquitin protease gene (USP6) (also known as TRE2 or TRE17) on chromosome 17p13. This suggests that most primary ABCs are associated with the upregulation of USP6, triggered by the robust activity of the CDH11 promoter.⁶ TRE17 induces the production of matrix metalloproteinase (MMP)-9 and MMP-10, contributing to ABC pathogenesis.⁷ In addition, TRE17 inhibits osteoblastic maturation, contributing to bone loss observed in ABC.⁸

Treatment options for primary ABC include both non-surgical and surgical approaches. Surgical options encompass curettage ± cavity filling and surgical resection.^4,⁹ Intralesional curettage carries a higher risk of local recurrence, usually within 6 to 12 months post-surgery.^2,4,9 Although en bloc resection is associated with a low recurrence rate, its practicality may be impeded by the lesion’s proximity to critical neural and vascular structures.^4,9 Less invasive interventions such as selective arterial embolization (SAE), sclerotherapy, intralesional injection, and radiation have shown favourable outcomes but some of these may be associated with significant morbidities.^4,5

Denosumab, a human monoclonal antibody, binds to the RANKL.¹⁰ RANKL, which activates the RANK receptor of osteoclasts, induces bone resorption. Thus, denosumab hinders RANK-RANKL interaction, suppressing osteoclast activity and replacing tumour stroma with densely new woven bone.¹⁰ The RANKL-RANK interaction has been associated with the pathogenesis of GCTB, where its osteoclast-like giant cells prominently express RANK.¹⁰ Considering the similarly elevated expression of RANK in the giant cells of ABCs, along with the heightened expression of RANKL in its’ neoplastic stromal cells, the potential application of denosumab therapy has been expanded to include ABCs.⁹

Denosumab is FDA-approved for multiple indications,¹¹ including the reduction of skeletal-related events (SREs) in patients with multiple myeloma and those with bone metastases from solid tumours. It is also approved for treating adult patients and skeletally mature adolescents with unresectable giant cell tumours of bone, or in cases where surgical resection would likely result in significant morbidity. Furthermore, denosumab is indicated for the treatment of osteoporosis in postmenopausal women and for glucocorticoid-induced osteoporosis. However, denosumab is not currently FDA-approved for ABCs due to the limited available literature.¹¹

Thus, in this scoping review, we systematically examined the existing literature on the utilisation of denosumab in ABCs. We aim to identify the types of evidence pertaining to denosumab’s application in ABCs, focusing on its role, treatment outcomes, and adverse effects. While two previous reviews, a narrative review¹² and a systematic review,⁵ have addressed the management of ABC with denosumab, our scoping review offers the most up-to-date and comprehensive analysis to date. With 29 articles (involving 67 patients), our review offers a broader perspective and captures the latest data, providing a more current understanding of ABC management with denosumab.

Materials and methods

Search strategies

This scoping review employed a rigorous search strategy aligned with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Extension for Scoping Reviews (PRISMA-ScR) checklist.¹³ The search was systematically conducted across five electronic databases: Scopus, Ovid MEDLINE, Ovid Embase, PubMed, and Web of Science (WoS), from inception to 31^st December 2023. To ensure comprehensive coverage of relevant literature, references from other published reviews and related published papers were meticulously reviewed to avoid missing any pertinent articles that may have been previously identified by other researchers. The Medical Subject Headings (MeSH) and keywords used were “Aneurysmal bone cyst” and “Denosumab”, in combination with Boolean operators AND/OR to refine and enhance the search.

Study selection and screening

All studies identified from the database searches were exported to a reference management software (EndNote 20), wherein duplicates were removed through the ‘Find Duplicates’ function. Two reviewers (VS, VAS) independently screened the titles and abstracts of all articles to remove review articles, conference abstracts, and studies that did not feature either ABC cases, denosumab use or both. Full-text screening of potentially pertinent studies was undertaken to evaluate adherence to the inclusion criteria, encompassing all peer-reviewed journal articles that included patients with primary ABCs treated with denosumab. Due to the scarcity of published literature on this subject, this review incorporated even case reports and case series with small sample sizes that contained the necessary parameters for analysis. Exclusion criteria involved secondary aneurysmal bone cysts, review articles, commentaries, editorials, conference abstracts, non-full text publications, non-English publications, animal and in-vitro models studies, and studies in which outcomes were not specified. Any discrepancies between the two reviewers were resolved by a third reviewer (AP). This systematic process identified the studies for final inclusion.

Data extraction and charting

Two investigators (VS, VAS) independently extracted and documented the data from each included study into a Microsoft Excel spreadsheet to minimise reporting bias. In instances of discrepancies, a third investigator (AP) intervened to resolve inconsistencies before the final findings from the specific study were recorded for further analysis.

The extracted data include the author’s name, year of publication, study type, sample size, age, gender, ABC site, presenting symptoms, interventions before denosumab (if any) and their corresponding outcome. Upon initiation of denosumab, the following data was extracted: dosage and duration of therapy, its role (neoadjuvant, primary treatment, second-line treatment or adjuvant role), clinical and radiological response, recurrence post-denosumab, adverse effect and duration of follow-up. In cases of tumour recurrences following denosumab treatment, additional data extracted included the timing of recurrence in relation to denosumab administration and the approach to managing recurrences. Similar data was gathered for patients who experienced hypercalcaemia and hypocalcaemia following denosumab treatment.

Synthesizing, analysing and results reporting

The information gathered was subsequently compiled, synthesized, and analysed. The results were then presented using tables. This review provided both quantitative and qualitative assessments of the study findings. Because of the highly heterogeneous data and diversity of research focus from included studies, which comprised case reports and case series, statistical analysis was not feasible. The Statistical Package for Social Sciences (SPSS, Chicago, IL, USA Version 20.0) was employed to create a database to analyse quantitative data.

Results

Study characteristics and demographics

The systematic searches across five databases initially revealed 390 peer-reviewed articles, as depicted in Figure 1. After removing 242 duplicates, we screened the titles and abstracts of 148 articles, subsequently excluding an additional 114 articles. Finally, a total of 34 articles underwent full-text review, of which 29 fulfilled the inclusion criteria and were ultimately included in the final review.^14–42 No non-English language publications were found.

Figure 1.

PRISMA study selection flowchart showing the total of publications removed at various stages and the reasons for the exclusions.

In total, 29 studies involving 67 patients (38 males, 29 females) were identified. Details of patient demographics, clinical features, treatment, and outcomes are presented in Table 1. All the included cases were presented as case reports (n = 16) or as part of a case series (n = 13). No randomized clinical trials were found among the selected studies. The mean age of patients was 16.8 years with a standard deviation (SD) of 9.3 years (range 5-50 years). The majority of patients (76.1%) were ≤18 years of age. In 42 cases (62.7%), the tumour involved the spine, making it the most common location for ABC in this scoping review. Of these, the cervical spine was the most common (n = 13), followed by the sacrum and lumbar (n = 9 each) and thoracic spine (n = 8). The next more common location was the pelvis (n = 7). Of the 53 cases that reported the presenting symptoms, the most common symptoms were pain (90.6%), followed by neurological symptoms (41.5%) and swelling (11.3%).

Table 1.

Patients’ demography, clinical characteristics, denosumab treatment & outcome.

Authors, year study type	Age (years) gender	Site	Presenting symptoms	Initial interventions before denosumab^a	Outcome of initial intervention	Denosumab treatment (role, dose, duration)	Clinical (C) & radiological (R) response	Recurrence post-denosumab	Adverse events	F/U (months)
Asi, 2018¹⁴ Case report	32, M	Maxillary sinus & skull base	Pain, epistaxis, neurologic symptoms	None	NA	Primary treatment	C-Yes R-Yes	No	No	18
						120 mg weekly for 1 month, then monthly
						Duration: 18 months
Bazan, 2022¹⁵ Case series	38, F 16, F	Spine (L3) Spine (T6)	NS	Resection (1) Curettage (1)	Recurrence (1)	Adjuvant (1)	C-Yes (2) R-Yes (2)	No	No	42
						Second-line (1)
						120 mg/month for >12 months
						Duration: 42 months (mean)
Bowen, 2019¹⁶	13, M	Tibia	NS	Curettage & bone graft	Recurrence	Second-line (1)	C-NS	NS	Generalized sclerotic metaphyseal bands	NS
Case report	13, M	Tibia	NS	Curettage & bone graft	Recurrence	Dose & duration: NS	R-Yes	NS	Generalized sclerotic metaphyseal bands	NS
Chan, 2022¹⁷ Case report	13, M	Spine (C2)	Neck pain	Excision & embolization	Unable to achieve complete excision	Adjuvant	C-Yes R-Yes	No	No	18
						Dose: NS
						Duration: Monthly for 6 months
Del Sindaco, 2021¹⁸	8, M	Spine (C4-C7)	Pain, neurologic symptoms	None	NA	Primary treatment	C-Yes	Yes	Hypercalcaemia & metaphyseal bands in long bones	60
Case report	8, M	Spine (C4-C7)	Pain, neurologic symptoms	None	NA	70 mg/m² weekly for 1 month, then monthly. Duration: 12 months	R-Yes	Yes	Hypercalcaemia & metaphyseal bands in long bones	60
Dubory, 2016¹⁹	26, F	Spine (C7-T1)	Pain, neurologic symptoms	Embolization & curettage	NS	Adjuvant	C-Yes	No	No	19.5 (mean)
Case series^b	26, F	Spine (C7-T1)	Pain, neurologic symptoms	Embolization & curettage	NS	120 mg monthly duration: 12.9 months (mean)	R-Yes	No	No	19.5 (mean)
Durr, 2019²⁰ Case series	6 cases	Spine(S) (2)	Pain (6)	Embolization (2)	Recurrence (4) No response (1)	Primary treatment (1) second-line (5)	C-Yes (2), NS (4)	Yes (2)	Hypercalcemia (1)	NS
	4F, 2M	Radius (1) femur (1)		Sclerotherapy (2)		120 mg d 1, 8, 15, 28 then monthly	R-Yes (4)
	Median age: 17	Talus (1) pelvis (1)		Curettage & bone grafting (4)		Duration: 12 months (median)	NS (2)
Fadavi, 2021²¹ Case report	13, M	Spine (C2)	Pain, swelling, neurologic symptoms	Resection, curettage, embolization & radiation	Recurrence	Second-line	C-Yes R-Yes	No	No	12
						120 mg monthly
						Duration: 12 months
Fontenot, 2018²² Case report	13, F	Fibula	Pain, swelling	Curettage & bone grafting	Recurrence	Second-line	C-Yes R-Yes	No	No	36
						120 mg monthly
						Duration: 12 months
Gajewski, 2023²³ Case report	12, F	Metacarpal	Pain, swelling	None	NA	Neoadjuvant	C-Yes R-Yes	No	No	41
						120 mg/monthly
						Duration: 12 months
Gandolfi, 2023²⁴ Case report	10, F	Spine (S)	Pain, neurologic symptoms	Embolization & curettage	Recurrence	Second-line	C-Yes R- NS	No	Hypercalcaemia Hypocalcaemia	6
						60 mg /dose for 22 doses: Weekly for 4 doses, every 4 weeks for 12 doses, and every 8 weeks for 6 doses
						Duration: 8.3 m
Ghermandi, 2016²⁵ Case series	42, M 16, M	Spine (L5)	Pain (2), neurologic symptoms (2)	Embolization	No response (2)	Second-line (2)	C-Yes (2) R-Yes (2)	No	No	34 (mean)
						120 mg/week for 1 month then monthly
						Duration: 13 & 11 cycles
Giantini-Larsen, 2022²⁶ Case series	16, F 21, M 18, F	Spine (2T, 1C)	Pain (3) & neurologic symptoms (1)	Embolization & resection (1)	Recurrence (1)	Neoadjuvant (3)	C-Yes (3) R-Yes (3)	No	No	37 (mean)
Giantini-Larsen, 2022²⁶ Case series	16, F 21, M 18, F	Spine (2T, 1C)	Pain (3) & neurologic symptoms (1)	Embolization & resection (1)	Recurrence (1)	Dose: NS, monthly for duration: 8 cycles	C-Yes (3) R-Yes (3)	No	No	37 (mean)
Harcus, 2020²⁷ Case report	13, M	Tibia	Pain, swelling	Curettage	Recurrence	Second-line	C-Yes R-Yes	No	Hypercalcaemia Hypocalcaemia	16
						70 mg/m² weekly for 1 month, then monthly for 6
						Months, followed by tapering dose
						Duration: 27 months
Hung, 2022²⁸	50, F	Spine (C2/3)	NS	None	NA	Neoadjuvant (2)	C- NS (2)	Yes (1)	NS	14 (mean)
Case series	28, M	Temporal bone	NS	None	NA	120 mg, 3-9 doses for 0.5 to 7 months duration: 4.5 months (median)	R- Yes (2)	Yes (1)	NS	14 (mean)
Kotaka, 2023²⁹ Case report	28, M	Spine (L3)	Pain	None	NA	Primary treatment	C-Yes R-Yes	Yes	No	37
						120 mg d 1, 8, 15, 29, then 60 mg/ monthly
						Duration: 3 months
Kulkarni, 2019³⁰ Case report	14, F	Spine (T5)	Pain, neurologic symptoms	Excision	Recurrence	Second-line	C-Yes R-Yes	No	NS	24
						120 mg d 1, 8, 15, 28 then monthly
						Duration: 6 months
Kurucu, 2018³¹ Case series	9 cases (5M,4 F) median age:12.5	Spine (3) CVJ (1) Pelvis (3) Mandible (1) Humerus (1)	Pain (7), swelling (3), limping (3), pathologic fracture (2)	Curettage & allograft (3), intralesional steroid (1)	Recurrence (3)	Primary treatment (6)	C- Yes (9) R-Yes (8)	Yes (2)	Hypercalcaemia (2), fatigue (2), mild GIT disorder (1), muscle pain (1)	29 (median)
						Second-line (3)
						70 mg/m² weekly for 1 month then monthly
						Duration: 12 months (median)
Lange, 2012³² Case series	8, M 11, M	Spine (C5) Spine (C5)	Pain (2), neurologic symptoms (2)	Curettage (2)	Recurrence (2)	Second-line (2)	C-Yes R-Yes	No	Hypocalcaemia (1)	3 (mean)
						70 mg/m² weekly, then monthly
						Duration: 3 months (mean)
Ntalos, 2017³³ Case report	35, F	Pelvis	Pain, neurologic symptoms	Embolization	NS	Neoadjuvant	C-Yes R-Yes	Yes	No	48
						60 mg monthly
						Duration: 12 months
Palmerini, 2018³⁴ Case series	9 cases 6M, 3F Median age: 17	Spine/pelvis (6) Ulna (1) tibia (1) Humerus (1)	Asymptomatic (1), pain (7), radiculopathy (1), Paraesthesia (1)	None	NA	Neoadjuvant (2)	C- Yes (9) R-Yes (9)	No	Vomiting (1)	23 (median)
						Primary treatment (7)
						120 mg d1, 8, 15, 21 then monthly
						Duration: 8 cycles (median)
Patel, 2018³⁵ Case report	16, M	Spine (C1)	Pain	Calcitonin & methylprednisolone intralesional injection	No response	Second-line	C- Yes R- Yes	No	No	12
						120 mg every monthly
						Duration: 12 months
Pauli, 2014³⁶ Case report	21, F	Radius	Pain, swelling	Curettage	Recurrence	Neoadjuvant	C- Yes R-Yes	Yes	No	48
						120 mg monthly
						Duration: 5 months
Pelle, 2014³⁷ Case report	5, M	Sacrum	Pain, neurologic symptoms	None	NA	Primary treatment	C- Yes R- Yes	No	No	12
						1.2 mg/kg/dose weekly for 1 month, then monthly
						Duration: 12 months
Raux, 2019³⁸ Case series	5 cases 3M, 2F Median age: 8	Spine (4) (2L,1S,1C) Femur (1)	Pain (5), neurologic symptoms (3)	Excision (3) sclerotherapy (1) Curettage & bone graft (1)	Recurrence (3)	Second-line (3)	C- Yes R- Yes	Yes (1)	Hypercalcemia (2) Hypocalcaemia: 1	24 (median)
						Neoadjuvant (1)
						Primary treatment (1)
						70 mg/m² weekly (4 times) then monthly
						Duration: 12months (median)
Skubitz, 2015³⁹ Case report	27, M	Spine (S)	Pain	None	NA	Primary treatment	C-Yes R-Yes	No	No	12
						120 mg d1, 8, 15, 28, then monthly
						Duration: 12 months
Sydlik, 2020⁴⁰ Case series	11, M 6, M	Spine (S) Femur	Pain (2) neurologic symptoms (1)	None	NA	Primary treatment (2)	C-Yes R-Yes	No	Hypercalcaemia (2)	36 (median)
						60 mg on days 1, 8, 15, 28, and then monthly
						Duration: 13 months (median)
Upfill‐Brown, 2019⁴¹ Case series^b	10, F	Pelvis	Pain	Curettage & bone graft	Recurrence	Second-line	C- Yes R- Yes	No	Hypercalcaemia Hypocalcaemia	13
						120 mg every 4 weeks, with additional loading doses on days 8, 15
						Duration: 12 months
Vanderniet, 2023⁴² Case series	7 cases 4M, 3F Mean age: 13.4	Spine (2C, 1L, 4T)	Pain (4), neurologic symptoms (3), Incidental finding (2), swelling (1)	Excision (3) Embolization (4) Sclerotherapy (3)	Improvement in symptoms (4) (3 others were asymptomatic from the start)	Adjuvant (4)	C- Yes (7) R- Yes (7)	No	Hypocalcaemia (5) Hypercalcaemia (3)	38.4 (mean)
						Primary treatment (3)
						70 mg/m², monthly for at least 6 months
						Duration: 16 months (mean)

NA, non-applicable; NS, not specified, FU; Follow-up; C, cervical; T, thorax; L, lumbar; S, sacrum; CVJ, costovertebral joint.

^aThe total may not align with the actual number of patients, as a single patient could undergo multiple interventions.

^bWhile termed a case series, the reported case is the only ABC, while the remaining cases are non-ABC.

Denosumab therapy

Among the 67 patients, denosumab served as the primary treatment in 25 patients (37.3%), as a second-line treatment in 24 (35.8%), as neoadjuvant therapy for 11 patients (16.4%) and as adjuvant therapy for seven patients (10.4%) (Tables 1 and 2). In the 25 patients from 11 studies^{14,18,20,29,31,34,37–40,42} where denosumab was administered as the primary and exclusive treatment, the decision was influenced by tumours deemed unresectable, challenging or high-risk to resect, or when surgical interventions carried the potential for complications. In one study, denosumab was used as the primary treatment in three patients with asymptomatic lesions.⁴² The vertebrae/pelvis were affected in 20 out of 25 patients who received denosumab as primary therapy (88%), and 76% of these patients were aged 18 or younger.

Table 2.

Denosumab therapy: Treatment categories and applications.

Authors	Age (years) Gender	Site	Reason denosumab given as primary treatment	Clinical/Radiological response after denosumab given as primary treatment
Asi, 2018¹⁴	32, M	Maxillary sinus & skull base	Surgical resection unfavourable (high-risk)	Clinical and radiological improvement
Del sindaco, 2021¹⁸	8, M	Vertebrae C4-C7	Tumour not resectable	Clinical and radiological improvement
Durr, 2019²⁰	6, M	Sacrum	Surgical resection unfavourable (high-risk)	Clinical and radiological improvement
Kotaka, 2023²⁹	28, M	Vertebrae L3	Surgical resection unfavourable (high-risk)	Clinical and radiological improvement
Kurucu, 2018³¹	17, F	Pubic ramus	High-risk of complications associated with surgeries	Clinical (n = 5) and radiological (n = 4) improvement
	12, M	Iliac bone
	5, F	Vertebrae C2
	6, M	Acetabulum
	16, F	Costovertebral junction
	10, F	Vertebrae L3
Palmerini, 2018³⁴	14, F	Sacrum	Inoperable tumour or high-risk of surgical complications	Clinical and radiological improvement
	16, M	Vertebrae L5-S1
	42, M	Spine
	16, F	Iliac wing
	12, M	Proximal ulna
	19, M	Proximal humerus
	25, M	Spine
Pelle, 2014³⁷	5, M	Sacrum	Challenges of surgery	Clinical and radiological improvement
Raux, 2019³⁸	8, M	Vertebrae C5, C6	Absence of any validated surgical or interventional radiological procedure for treatment of ABCs involving the cervical spine	Clinical and radiological improvement
Skubitz, 2015³⁹	27, M	Sacrum	Surgery was considered to have a high risk of serious permanent morbidity and disability	Clinical and radiological improvement
Sydlik, 2020⁴⁰	11, M	Sacrum	Surgical treatment was difficult owing to the localisation and extension of the tumour	Clinical and radiological improvement
Sydlik, 2020⁴⁰	6, M	Femur		Clinical and radiological improvement
Vanderniet, 2023⁴²	14, M	Vertebrae C3	Denosumab given as primary treatment as lesions were asymptomatic	Radiological improvement (clinically asymptomatic)
	11, F	Vertebrae T1
	18, M	Vertebrae T9

Authors, year study type	Age (years) gender	Site	Reason denosumab given as neoadjuvant treatment	Outcome on tumour after denosumab given as neoadjuvant treatment
Gajewski, 2023²³	12, F	Metacarpal	To facilitate resection	Denosumab resulted in considerable lesional calcification with a well-defined border that was more amenable to resection and reconstruction
Giantini-Larsen, 2022²⁶	16, F	Vertebrae T9	Tumour surgically unresectable	Denosumab resulted in calcification and devascularization of lesions, allowing for safer, more complete resection
	21, M	Vertebrae C4, C5
	18, F	Vertebrae T12
Hung, 2022²⁸	50, F	Vertebrae C2/3	To facilitate resection	After denosumab, both tumours showed decrease in tumour size with increased ossification and mineralization, facilitating resection
Hung, 2022²⁸	28, M	Temporal bone	To facilitate resection
Ntalos, 2017³³	35, F	Pelvis	Tumour surgically inoperable	Denosumab led to significant shrinkage of the lesion, which allowed surgical intervention
Palmerini, 2018³⁴	19, M	Proximal humerus	Facilitate surgical resection	Not stated
Palmerini, 2018³⁴	17, F	Distal tibia	Facilitate surgical resection	Not stated
Pauli, 2014³⁶	21, F	Radius	Facilitate resection	After denosumab, tumour was better circumscribed and clearly demarcated by a bony rim leading to the feasibility of a complete resection of the tumour
Raux, 2019³⁸	14, F	Vertebrae S2, S3	Facilitate surgical resection as tumour was large and extended into sacral canal	Denosumab resulted in mineralization of lesion, facilitating surgery

Authors, year	Age (years) gender	Site	Reason denosumab given as second-line treatment	Clinical/Radiological response after denosumab given as second-line treatment
Bazan, 2022¹⁵	38, F	Vertebrae L3	Recurrence after surgery	Clinical and radiological improvement
Bowen, 2019¹⁶	13, M	Tibia	Tumour continued to grow, despite 2 times curettage	Radiological improvement (clinical not specified)
Durr, 2019²⁰	18, M	Sacrum	Recurrence/no improvements after initial treatment which included curettage & bone graft, sclerotherapy and embolization	Clinical improvement (1), not specified (4)
	30, F	Pelvis		Radiological improvement (3), not specified (2)
	16, F	Talus
	15, F	Distal radius
	16, F	Distal femur
Fadavi, 2021²¹	13, M	Vertebrae C2	Symptoms persisted despite curettage, embolization & radiation therapy	Clinical and radiological improvement
Fontenot, 2018²²	13, F	Fibula	Recurrence despite 2x curettage & bone graft	Clinical and radiological improvement
Gandolfi, 2023²⁴	10, F	Sacrum	Failure of curettage and embolization and ongoing symptoms	Clinical improvement after denosumab (radiological not specified)
Ghermandi, 2016²⁵	42, M	Vertebrae L5-S1	Failed selective arterial embolization of tumour (surgery was avoided as it was deemed high-risk)	Clinical and radiological improvement
Ghermandi, 2016²⁵	16, M	Vertebrae L5		Clinical and radiological improvement
Harcus, 2020²⁷	13, M	Tibia	Recurrence after curettage (3x)	Clinical and radiological improvement
Kulkarni, 2019³⁰	14, F	Vertebrae (T5)	Recurrence after surgical excision	Clinical and radiological improvement
Kurucu, 2018³¹	16, M	Mandible	Recurrence after other medical and/or surgical treatments which included curettage and corticosteroid	Clinical and radiological improvement
	8, M	Humerus
	16, M	Sacrum
Lange, 2012³²	8, M	Vertebrae C5	Recurrence after intralesional tumour resection	Clinical and radiological improvement
Lange, 2012³²	11, M	Vertebrae C5	Recurrence after intralesional tumour resection	Clinical and radiological improvement
Patel, 2018³⁵	16, M	Vertebrae C1	No clinical and radiological improvement after intra-lesional injection of calcitonin and methylprednisolone	Clinical and radiological improvement
Raux, 2019³⁸	8, M	Vertebrae L4	Repeated recurrence following other medical and/or surgical treatments which included excision, curettage and sclerotherapy.	Clinical and radiological improvement
	7, F	Femoral neck
	17, M	Vertebrae L3
Upfill‐Brown, 2019⁴¹	10, F	Pelvis	Recurrence after curettage and bone graft (2x)	Clinical and radiological improvement

Authors, year	Age (years)Gender	Site	Reason denosumab given as adjuvant therapy	Clinical/Radiological response after denosumab given as adjuvant therapy
Bazan, 2022¹⁵	16, F	Vertebrae T6	Denosumab given with intralesional surgery	Clinical and radiological improvement
Chan, 2022¹⁷	13, M	Vertebrae C2	Denosumab given post-op denosumab to control the tumour growth as unable to achieve complete excision surgically	Clinical and radiological improvement
Dubory, 2016¹⁹	26, F	Vertebrae C7-T1	Denosumab given as adjuvant with curettage and artery embolization	Clinical and radiological improvement
Vanderniet, 2023⁴²	12, M	Vertebrae C3	Denosumab given for residual lesions with combination of other therapies which included surgical resection, embolization, sclerotherapy	Clinical and radiological improvement
	14, F	Vertebrae T1
	13, M	Vertebrae T2
	12, F	Vertebrae T4

In 11 cases from seven studies,^{23,26,28,33,34,36,38} denosumab functioned as a neoadjuvant therapy. These studies showed that neoadjuvant denosumab led to reduced tumour size, increased calcification, lesion devascularization, and better delineation of the tumours by a bony rim, enhancing the safety, feasibility, and completeness of the subsequent resection.

In 24 cases involving 14 studies,^{15,16,20–22,24,25,27,30–32,35,38,41} denosumab was administered as a second-line therapy either because of tumour recurrence, failed initial treatment or poor clinical/radiological response to initial interventions. These cases responded positively to subsequent denosumab therapy. Finally, in seven cases,^15,17,19,42 denosumab served as an adjunct to other treatment modalities.

Amongst the other interventions used for the second-line and adjuvant groups, curettage (n = 18) was the most frequently employed, followed by arterial embolization (n = 12), tumour resection/excision (n = 10), and sclerotherapy (n = 6). These interventions were administered either alone or in different combinations. Among the combined approaches, the most frequent was the combination of surgery (curettage/excision) and selective embolization (n = 7).

Regarding denosumab administration, Table 1 reveals considerable diversity in the dosage, frequency, and duration of denosumab administration. As shown in Tables 1 and 2, all 60 patients with clinical responses reported, exhibited positive outcomes, primarily in pain and neurological symptom improvement. Likewise, 98% of the 64 patients with documented radiological outcomes demonstrated improvement after denosumab treatment.

Tumour recurrence

As illustrated in Table 3, in total, there were 10 tumour recurrences identified among the 67 patients (15%) who received denosumab treatment.^{18,20,28,29,31,33,36,38} The mean age of these cases was 20.9 years ±SD 9.2 (range 8-35 years). The tumour recurred in the following sites: pelvis (n = 3), cervical spine (n = 2) and one each at the sacral, lumbar, radius, temporal bone, and costovertebral junction. Prior to the 10 recurrences, denosumab was administered as primary treatment in five patients, as neoadjuvant therapy in three, and as second-line therapy in two patients. Hence, recurrence was noted in three out of 11 patients administered denosumab as neoadjuvant therapy, five out of 25 patients treated with denosumab as primary therapy, two out of 24 patients who received it as second-line therapy, and none in the adjuvant group.

Table 3.

Recurrence post-denosumab and its management.

Authors, Year	Age (years)Gender, Site	Initial treatment (before denosumab)	Initial denosumab treatment (Role, dose duration)	Time of recurrence post-denosumab	Management of recurrence
Del sindaco, 2021¹⁸	8, M	None	Denosumab given as primary treatment	9 months after denosumab stopped	Denosumab was restarted and after 2.5 years at a tapering dose, treatment was stopped because of long-term tumour control
Del sindaco, 2021¹⁸	Spine (C)	None	Dose: 70 mg/m² weekly for 1 month, then monthly, Duration:12 months	9 months after denosumab stopped
Durr, 2019²⁰	18, M	Polidocanol injection and embolization	Denosumab started as second-line treatment	One year after denosumab stopped	Denosumab was restarted. 18 months later, the dosage was reduced. Total duration NS.
Durr, 2019²⁰	Spine (S)	Polidocanol injection and embolization	Dose: 120 mg weekly for 1 month, then monthly for 12 months. Dose tapered for another 12 months, duration: 24 months	One year after denosumab stopped
Durr, 2019²⁰	30, F	Curettage was done twice as there were two recurrences	Denosumab started as second-line treatment	At 8 months of denosumab, while treatment was ongoing	Initial recurrence was treated with curettage and bone grafting; denosumab was postponed initially due to pregnancy. 18 months post-surgery, second recurrence occurred & denosumab was initiated, but discontinued due to second pregnancy. Post-pregnancy, there was another recurrence, prompting denosumab resumption
Durr, 2019²⁰	Pelvis	Curettage was done twice as there were two recurrences	Dose: 120 mg weekly for 1 month, then monthly	At 8 months of denosumab, while treatment was ongoing
Hung, 2022²⁸	28, M	None	Denosumab given as neoadjuvant treatment, with curettage performed 3 months after last dose	8 months after curettage	Received 2 additional doses of 120 mg denosumab & a second surgical curettage 2 months later
Hung, 2022²⁸	Temporal	None	Dose: 120 mg, 3 doses	8 months after curettage
Kotaka, 2023²⁹	28, M	None	Denosumab given as primary treatment	17 months after denosumab stopped	Denosumab restarted. Follow-up after 37 months showed no recurrences
Kotaka, 2023²⁹	Spine (L)	None	Dose: 120 mg d 1, 8, 15, 29, then 60 mg/ monthly, duration: 3 months	17 months after denosumab stopped
Kurucu, 2017³¹	17, F	None	Denosumab given as primary treatment	3 months after denosumab stopped	Sclerotherapy for clinical recurrence
Kurucu, 2017³¹	Pelvis	None	Dose: 70 mg/m² weekly for 1 month then monthly, duration: 14 months	3 months after denosumab stopped	Sclerotherapy for clinical recurrence
Kurucu, 2017³¹	16, F	None	Denosumab given as primary treatment	16 months after denosumab stopped	Denosumab was restarted. Currently on 6 months of treatment, with surgery planned upon tumour shrinks to operable size
Kurucu, 2017³¹	Costo-vertebral junction	None	Dose: 70 mg/m² weekly for 1 month then monthly, duration: 12 months	16 months after denosumab stopped
Ntalos, 2017³³	35, F	Arterial embolization	Denosumab given as neoadjuvant therapy, with surgical curettage performed after lesion shrinkage	6 months after curettage	Denosumab was restarted and discontinued at 17 months as patient developed hypocalcaemia. Follow-up after 15 months showed no recurrence
Ntalos, 2017³³	Pelvis	Arterial embolization	Dose: 60 mg monthly, duration: 12 months	6 months after curettage
Pauli, 2014³⁶	21, F	Curettage	Denosumab given as neoadjuvant treatment, with surgery performed 5 months after first dose	19 months after the second surgery	Denosumab was restarted. Follow-up at 4 years indicates a good response to treatment
Pauli, 2014³⁶	Radius	Curettage	Dose: 120 mg monthly, duration: 5 months	19 months after the second surgery
Raux, 2019³⁸	8, M	None	Denosumab was given as primary treatment	10 months after denosumab stopped	Denosumab restarted. Follow-up at 1 year indicates a good response to treatment
Raux, 2019³⁸	Spine (C)	None	Dose: 70 mg/m² weekly for 1 month then monthly, duration: 12 months	10 months after denosumab stopped

Six (of the 10 recurrences) occurred after denosumab discontinuation,^{18,20,29,31,38} at a mean duration of 11.2 ± SD 5.1 months post-cessation. The mean duration of denosumab administration for these six cases was 12.8 months ±SD 6.7 (range 3-24 months). Denosumab served as the primary treatment in five, while in one case, denosumab was administered as a second-line treatment. Of these, four recurrences occurred within 12 months, and two more within 12 to 24 months (range 3-17 months). Following the recurrences, denosumab was reintroduced in five out of the six cases, whereas in one patient, recurrence was treated with sclerotherapy.

Another three (of the 10) recurrences occurred following surgery after neoadjuvant denosumab therapy,^28,33,36,with an average duration of 11 months post-surgery (range: 6-19 months). In two of these cases, recurrence was treated by resuming denosumab, while the third patient’s recurrence was managed using a combination of denosumab and curettage.

The tenth recurrence occurred in a 30-year-old female who experienced recurrence 8 months into denosumab therapy while treatment was ongoing.²⁰ Surgery was the primary intervention for the initial recurrence, and the commencement of denosumab treatment was postponed due to the patient’s pregnancy. Following a second recurrence 18 months post-surgery, denosumab was started; however, it was discontinued again due to the onset of her second pregnancy. A third recurrence occurred post-pregnancy, prompting denosumab resumption. In addition to the 10 recurrences outlined above, in a 10-year-old child, the tumour persisted in advancing despite undergoing 6 months of denosumab treatment.³¹ Subsequently, denosumab was discontinued, and she underwent surgery. In total, less than half of the studies (21 studies comprising 31 cases) had a median/mean follow-up duration of more than 2 years.

Adverse events

The overall denosumab-related adverse events are shown in Table 1. Among these, 10 patients experienced hypocalcaemia,^{24,27,32,38,41,42} 14 had hypercalcemia,^{18,20,24,27,31,38,40–42} and two children manifested with sclerotic metaphyseal bands.^16,18 Table 4 displays the data pertaining to patients with hypocalcaemia. All 10 patients with hypocalcaemia were in the paediatric age range, spanning from 8 to 14 years. In seven cases, hypocalcaemia developed within the initial 2 months after the commencement of denosumab, while the timing was unspecified in three cases. In eight cases, hypocalcaemia manifested despite receiving prophylactic calcium and cholecalciferol supplementation, while the other two patients were not on any initial calcium supplements. Episodes of hypocalcaemia were treated by increasing the dose of calcium supplements in patients already on calcium supplements (n = 7) and starting calcium supplements (n = 1), while in two other patients, hypocalcaemia resolved without further treatment. Apart from experiencing episodes of hypocalcaemia, five of these patients also encountered episodes of hypercalcemia at different stages during their denosumab treatment.

Table 4.

Hypocalcaemia as an adverse effect of denosumab & its treatment.

Author, year	Age (years) gender	Initial denosumab treatment & calcium/Vit D supplementation	Hypocalcaemia episode and timing in relation to denosumab	Treatment of hypocalcaemia
Gandolfi, 2023²⁴	10, F	60 mg /dose for 22 doses: Weekly for 4 doses, every 4 weeks for 12 doses, and every 8 weeks for 6 doses. (Denosumab supplemented with calcium 24 mg/kg/day and 1000 IU Vit D/daily)	2 episodes of hypocalcaemia (timing not specified)	Normalized without further intervention
Harcus, 2020²⁷	13, M	70 mg/m2 weekly for 1 month, then monthly for 6 months, followed by tapering dose	1 episode of asymptomatic hypocalcaemia at early stages of denosumab (timing not specified)	Calcium carbonate 1.25 g/daily
Lange, 2012³²	8, M	70 mg/m2 monthly (denosumab supplemented with 500 mg calcium/daily and 1000 IU Vit D/daily)	1 episode of hypocalcaemia (timing not specified)	Increasing calcium dosage to 1000 mg/day
Raux, 2019³⁸	8, M	70 mg/m2 weekly (4 times) then monthly	1 episode of hypocalcaemia, 2 months after denosumab started	Increasing calcium dosage
Raux, 2019³⁸	8, M	(Denosumab supplemented with calcium & Vit D)		Increasing calcium dosage
Upfill‐Brown, 2019⁴¹	10, F	120 mg every 4 weeks, with additional loading doses on days 8, 15	1 episode of asymptomatic hypocalcaemia in the first month of therapy	Serum calcium normalized within 2 months without intervention
Vanderniet, 2023⁴²	12, M	70 mg/m2, monthly for at least 6 months (denosumab supplemented with 500 mg calcium/twice daily and 1000 IU Vit D/daily)	5 patients had asymptomatic hypocalcaemia 1 to 3 weeks after the first denosumab dose	Increasing calcium supplementation
	14, M
	14, F
	13, M
	12, F

Table 5 presents the details of 14 patients who developed hypercalcaemia, with 13 episodes^{18,20,24,31,38,40–42} arising after denosumab discontinuation and one while increasing denosumab dosing interval.²⁷ All cases (10 males and 4 females) occurred in the paediatric population with a mean age of 10.3 ± 2.9 years (range 6 to 16 years). The first episode of hypercalcaemia occurred at a mean of 4.8 ± 1.3 months (2.5 to 6 months) after denosumab was discontinued. The mean duration of denosumab therapy for these patients was 15.3 ± 5.1 months (range 12 to 30 months). The 14^th case involved a 13-year-old girl who developed hypercalcaemia on increasing the denosumab dose interval to 6 months from the earlier weekly, monthly, two-monthly and three-monthly intervals. Of the 14 hypercalcaemic patients, six experienced three episodes of hypercalcemia, seven encountered a single episode, and one developed two episodes of hypercalcemia.

Table 5.

Hypercalcaemia as adverse effect of denosumab & its treatment.

Author, year	Age (years)Gender	Initial denosumab treatment	Hypercalcaemia episode and timing in relation to denosumab	Treatment of hypercalcaemia
Del sindaco, 2021¹⁸	8, M	Initial treatment: 70 mg/m² weekly (4 times) then monthly, duration: 12 months	3 episodes of severe hypercalcaemia. The 1^st episode was 6 months after denosumab (initial treatment) was stopped. The 2^nd (after restarting denosumab while on tapering dose) and 3^rd (45 days after last denosumab dose) episodes were related to treatment of recurrence	1^st episode: Furosemide and IV infusion of zoledronic acid 2^nd episode: IV fluids and furosemide 3^rd episode: Zoledronic acid, stat dose and then 6 monthly (4 doses so far and calcium remains stable)
Del sindaco, 2021¹⁸	8, M	Recurrence: 70 mg/m² weekly (4 times) then monthly, then every 2 months, and finally every 3 months, duration: 30 months
Durr, 2019²⁰	6, M	60 mg every 4 weeks with two additional doses on days 8 and 15, duration: 12 months	1 episode of severe hypercalcaemia, 6 months after last denosumab dose	Patients required intensive care treatment (details of treatment not specified)
Gandolfi, 2023²⁴	10, F	60 mg /dose for 22 doses: Weekly for 4 doses, every 4 weeks for 12 doses, and every 8 weeks for 6 doses	3 episodes of hypercalcaemia; 108 days, 121 days & 135 days after denosumab stopped	1^st episode: IV fluids, furosemide, pamidronate (1 mg/kg) 2^nd episode: IV fluids, furosemide, pamidronate (1 mg/kg) & methylprednisolone (1 mg/kg 2x daily, 5 days) 3^rd episode: Zoledronic acid 0.03 mg/kg (1 dose), methylprednisolone (1 mg/kg 2x daily, 3 days) & IV fluids. Patient remained normocalcemic, 6 months post discharge
Harcus, 2020²⁷	13, M	70 mg/m² weekly for 1 month, then monthly for 6 months, and increasing dose interval to 2 monthly, 3 monthly and 6 monthly. Total: 17 doses over 27-month period with increasing dose interval	3 episodes of severe hypercalcaemia on increasing dosing interval to 6 months	1^st episode: IV fluids, furosemide & calcitonin had limited effect. Two doses of pamidronate (0.25 mg/kg and 0.5 mg/kg, 24 h apart) normalized calcium in 3 days 2^nd episode: Pamidronate (0.5 mg/kg) 3^rd episode: Zoledronic acid (0.05 mg/kg) No recurrence in 16 months since the last denosumab dose and 9 months since the last hypercalcemia episode
Kurucu, 2017³¹	2 cases 17, F 12, M	70 mg/m² weekly for 1 month then monthly, duration: 12 months (median)	Severe hypercalcemia in both patients, 5 months after denosumab stopped	IV fluids and bisphosphonates
Raux, 2019³⁸	8, M	70 mg/m² weekly (4 times) then monthly, duration: 17 months	3 episodes of hypercalcaemia: 3, 5 & 6 months after last denosumab dose	Bisphosphonate therapy
Raux, 2019³⁸	8, M	70 mg/m² weekly (4 times) then monthly, duration: 12 months	1 episode of hypercalcaemia, 5 months after last denosumab dose	NS
Sydlik, 2020⁴⁰	11, M	60 mg on days 1, 8, 15, 28, and then monthly, duration: 17 months	2 episodes of severe hypercalcaemia (2 weeks apart). The first was 76 days after last denosumab dose	Both episodes treated with neridronate 2 mg/kg infusion. Additionally, prednisolone and furosemide were administered. No recurrence on 1-year follow-up
Sydlik, 2020⁴⁰	6, M	60 mg on days 1, 8, 15, 28, and then monthly, duration: 12 months	3 episodes of hypercalcaemia. The first was 3 months after last denosumab dose	Restarted on denosumab repeatedly (3 courses) due to relapses of hypercalcemia every time denosumab stopped
Upfill‐Brown, 2019⁴¹	10, F	120 mg every 4 weeks, with additional loading doses on days 8 and 15, duration: 12 months	3 episodes of hypercalcaemia. The first was 5 months after last denosumab dose	1^st episode: Bisphosphonates, furosemide, and calcitonin 2^nd and 3^rd episodes: Corrected with furosemide
Vanderniet, 2023⁴²	3 cases 12, M 11, F 13, M	70 mg/m², 4-weekly for at least 6 months, duration: 16 months (mean) (This was followed by 2 doses of zoledronate 0.025 mg/kg to prevent rebound hypercalcaemia)	3 patients developed hypercalcaemia 5 to 7 months after denosumab stopped	Treated with zoledronate 0.025 mg/kg, with 2 patients requiring a second dose due to recurrence after first dose. This was followed by oral risedronate for 2–6 months with no further hypercalcaemia episodes

As shown in Table 5, bisphosphonates (single or repeated dose), which included zoledronate, pamidronate, neridronate, and risedronate, were the most used therapy (n = 11) in controlling hypercalcemia, even in patients experiencing multiple episodes of hypercalcemia. Other treatment approaches involved intravenous hydration and the administration of furosemide (n = 5) and the addition of calcitonin (n = 2) and/or prednisolone (n = 2) in a few cases. For one patient⁴⁰ who developed three episodes of hypercalcemia, the strategy involved repeatedly reinstating denosumab to manage hypercalcemia after each recurrence. Notably, Vanderniet et al.⁴² documented three cases wherein symptomatic hypercalcemia occurred despite the prophylactic administration of two doses of zoledronate following the last denosumab dose.

Other reported adverse events (Table 1) included sclerotic metaphyseal bands in two children aged 8 and 13 years. Additional minor side effects included fatigue (n = 2), mild gastrointestinal issues (n = 1), muscle pain (n = 1), and vomiting (n = 1).

Discussion

Our scoping review presents the most current and comprehensive evaluation of denosumab use in managing ABC. The results indicate that denosumab shows promise as an effective treatment for ABC, particularly in high-risk locations like the spine and pelvis. This study highlights its diverse applications, including use as a primary treatment, neoadjuvant therapy, second-line intervention after inadequate initial treatments, and adjunct therapy; with favourable clinical and radiological outcomes observed in the patients. However, the occurrence of tumour recurrences and adverse effects such as hypocalcaemia and rebound hypercalcemia, particularly in paediatrics patients, highlights the need for careful patient monitoring and extended follow-ups. Traditionally, the standard treatment for ABC has been curettage and filling the cavity with bone graft or polymethylmethacrylate remains the standard therapeutic approach.^2,43 However, it carries a 20%-30% risk of local recurrence.^43,44 There is an emerging trend toward minimally invasive procedures such as selective arterial embolization, sclerotherapy, and calcitonin ±corticosteroids injections.^31,43,44 Denosumab, with its expanding role, presents a relatively new alternative, particularly in surgically challenging sites such as the spine or sacrum.⁴³

Our scoping review found only case reports and case series, with no published clinical trials examining the use of denosumab in ABC. The majority (76.1%) of patients were aged ≤18 years, consistent with the age distribution observed in previous demographics of ABC.² However, there existed variations in tumour location in this review compared to the typical demography of ABC cases. While Mankin et al.² identified the tibia, femur and fibula as the most prevalent sites, our review revealed that the spine (62.7%) was the most common site, followed by the pelvis (10.4%). There is an obvious selection bias in our review and the observed difference likely arises from the challenges encountered in achieving curative resections of axial ABCs, where accessibility and anatomical constraints from neighbouring critical structures often hinder surgical interventions, thus favouring denosumab treatment as a preferable option.

In most cases in this review, denosumab was administered as the primary treatment (n = 25, 37.5%). In seven of the nine cases outlined by Palmerini et al., denosumab served as the primary treatment for inoperable tumours.³⁴ All seven cases showed clinical and radiological improvement with bone formation, ultimately obviating the need for surgical intervention. Vanderniet et al.⁴² detailed three patients who received denosumab as the primary intervention due to the asymptomatic nature of their lesions, resulting in ossification and stabilization of the ABC’s size. In another case series, Kurucu et al. detailed nine patients, of which denosumab was used as primary treatment in six cases for tumours involving the vertebrae and pelvis.³¹ In all cases, there was a regression of clinical symptoms within 3 months, with radiological improvement. In 35.8% (n = 24) of cases, denosumab was administered as second-line treatment after recurrence or inadequate responses following initial interventions, which included intralesional curettage, arterial embolization, excision, and sclerotherapy, either individually or in combination. In another 11 patients (16.4%), denosumab was utilized as a neoadjuvant therapy to enhance the ease and feasibility of tumour resection. In a case series involving three patients with unresectable spinal ABC, neoadjuvant denosumab was used to calcify, devascularize and decrease the size of these lesions, facilitating a safer and more thorough resection process.²⁶ Following denosumab administration in a 21-year-old woman with radius ABC; the tumour became delineated by a bony rim, facilitating resection and limb-preserving surgery.³⁶ In another case involving metacarpal ABC, denosumab reduced tumour size and induced calcification for successful resection and reconstruction.²³ Likewise, Raux et al.³⁸ reported a 14-year-old female with a large sacral ABC extending into the spinal canal. Neoadjuvant denosumab resulted in mineralization and cortical thickening, enabling surgical decompression and curettage.

It is important to highlight that irrespective of the denosumab regimen used, there was consistent clinical improvement, with all cases experiencing relief from pain and neurological symptoms. This will likely contribute to improvement in their functional ability and quality of life. In addition, where data was available, 98% of cases showed favourable radiological assessment after denosumab administration. Our scoping review demonstrated 10 recurrences (15%) after denosumab therapy: six occurring post-denosumab cessation, three following surgeries post-neoadjuvant denosumab, and one during ongoing denosumab treatment. Although small case numbers present challenges in drawing definitive conclusions, our data suggests that most recurrences arose within 2 years post-denosumab cessation. However, the majority of the studies included in this review indicated an average follow-up period of 2 years or less, potentially leading to an underestimation of the actual recurrence rate. Thus, longer follow-ups may provide a more accurate understanding of recurrence, guiding more informed treatment strategies. Notably, Mak et al. observed that while denosumab effectively suppressed the RANKL expression on osteoclasts, the proliferation of neoplastic stromal cells persisted unabated, suggesting their resilience in driving recurrence.⁴⁵

Treatment approaches for ABC have demonstrated recurrence rates ranging from 5% to 22%. For instance, Mankin et al. reported a recurrence rate of 22% among 121 ABC patients treated with curettage ± grafting. In comparison, patients who underwent resection exhibited a lower recurrence rate of 5%.² In a meta-analysis by Cruz et al., the recurrence risk after selective arterial embolization and sclerotherapies was 19% and 6%, respectively.⁴⁶

Our literature review identified 14 cases of hypercalcemia, 10 cases of hypocalcaemia, and two cases of sclerotic metaphyseal bands. There are several reported cases of hypercalcemia arising after discontinuation of denosumab treatment used for diseases such as GCTB, fibrous dysplasia, juvenile Paget’s disease, osteoporosis, osteogenesis imperfecta type VI.^18,47 Of the 14 instances of hypercalcemia, 13 occurred between 2.5 and 6 months following denosumab cessation, while one occurred while increasing the dosing interval. Although adult patients accounted for 24% of the patients included in this review, none of the adults experienced hypercalcaemia. All reported cases were confined to the paediatric age range, with a notable male predominance of 71%. Likewise, a systematic review encompassing 49 instances of rebound hypercalcemia post-denosumab discontinuation revealed that 82% of cases occurred in skeletally immature individuals.⁴⁷ Additionally, the duration between denosumab cessation and the onset of hypercalcemia was notably shorter in this subset of patients. Consistent with our finding, a significantly higher number of males among the skeletally immature patients presented with hypercalcemia.⁴⁷ This trend could be linked to higher bone mass typically found in males, resulting in increased calcium storage while on denosumab during the growth phase.^47,48 Hypercalcemia following denosumab withdrawal is likely due to the rapid recovery of osteoclastic activity, leading to accelerated bone resorption and calcium release into the bloodstream.⁴⁷ Skeletally immature children, with their inherently higher baseline bone turnover, are likely to be more susceptible to rebound osteoclastic activity, consequently resulting in a higher incidence of rebound hypercalcemia.^47,49

While there are currently no standardized treatment guidelines, addressing denosumab-induced rebound hypercalcemia entails a multifaceted approach. In this review, a range of treatments, including intravenous hydration, diuretics, calcitonin, corticosteroids, bisphosphonates, and/or repeated dosages of denosumab, were utilized. The prophylactic administration of bisphosphonates is often employed to avert the recurrence of rebound hypercalcemia. Bisphosphonates integrate into the bone matrix, thereby modulating osteoclast activity upon discontinuing denosumab treatment. Nevertheless, rebound hypercalcemia may still occur despite this preventative measure.⁴² Hypercalcemia may also be averted by gradually tapering the dosage of denosumab instead of abruptly stopping it.^18,20,27,31 Currently, there are no established guidelines for timing and frequency of monitoring during denosumab therapy,²⁴ however, regular follow-ups are recommended upon starting and treatment withdrawal based on literature evidence. Additionally, it is important to educate patients and their families about the symptoms of hypercalcemia to ensure prompt identification and appropriate treatment.²⁴

This review also revealed that 10 paediatric patients (aged 8 to 14 years) experienced hypocalcaemia during the initial phases of denosumab therapy despite eight of them being administered prophylactic calcium and cholecalciferol. Treatment consisted of either escalating the dosage or commencing calcium supplements. In two instances, hypocalcaemia spontaneously resolved. Other reported adverse events included the formation of sclerotic metaphyseal bands in two children. While osteonecrosis of the jaw and atypical femoral has been documented,^34,49 our review did not identify any such complications. However, mild symptoms like fatigue, minor gastrointestinal discomfort, muscle pain, and vomiting were reported.

Concerns have been raised regarding the potential of denosumab to disturb skeletal development in patients whose growth plates have yet to close. This includes disruptions in linear growth, dental development, and ossification of growth plates.²⁰ Despite this, our review found no evidence of impaired linear growth. However, there remains a paucity of data regarding the effects of denosumab on growth plates and linear growth, an area that needs further exploration.³¹ In a histopathological study, there was persistent epiphyseal activity throughout and after denosumab therapy, coupled with the reversal of bone turnover suppression upon treatment cessation, implying denosumab did not induce substantial adverse effects on growth.⁵⁰ Considering that most cases in our review were followed up for less than 2 years, conducting longer-term follow-up to detect such adverse effects would be advisable.

This scoping review had several limitations. Firstly, the studies primarily consisted of case reports and case series. Notably, there have been no clinical trials investigating the relationship between denosumab and ABC thus far. Thus, the level of evidence-based substantiation was not high, necessitating cautious interpretation of any resulting conclusions. The data from the various studies exhibited considerable heterogeneity, including variations in the duration and total doses of denosumab, as well as the different approaches to its administration. Thus, conducting statistical analysis or meta-analysis proved unfeasible. Instead, we provided quantitative and descriptive evidence of the data.

The strengths of this review included systematic database search and meticulous data extraction, with clearly defined inclusion and exclusion criteria. Although a previous systematic review on denosumab use in ABC was published,⁵ it did not categorize denosumab therapy based on treatment context—primary, neoadjuvant, second-line, or adjuvant. Our review introduces this framework, offering deeper insights into the rationale behind initiating denosumab in each category. This distinction is important for understanding how denosumab’s role varies with different treatment aims, which is essential for individualized care. For instance, denosumab is utilized in neoadjuvant therapy to shrink the lesion prior to surgery, whereas in second-line therapy, it is employed to address tumour recurrence or manage refractory cases. This categorization enhances our understanding of how denosumab can be tailored to distinct clinical scenarios, which is especially important in relatively rare conditions like ABC, where appropriate treatment plans can significantly influence outcomes. Additionally, while the previous systematic review did address side effects of denosumab such as hypercalcemia, it lacked details on the timing and management of these episodes. Our review fills this gap by offering a comprehensive analysis of hypercalcemia, detailing its frequency, timing relative to denosumab administration, and the interventions used to manage it. This provides clinicians insights into managing such complications. Furthermore, since the earlier review, 22 additional cases of ABC treated with denosumab have been reported over the last 4 years. Thus, our review represents the most comprehensive and up-to-date synthesis, incorporating the largest pool of studies available. It offers new insights into the complex relationship between denosumab and ABC, while addressing the gaps identified in previous reviews.

Conclusions

In conclusion, this scoping review highlights the effectiveness of denosumab in managing aneurysmal bone cysts, suggesting notable improvements in both clinical and radiological outcomes. Denosumab might be considered a treatment option, particularly for cases involving spinal and pelvic tumours with significant surgical risks and unresectable tumours. Other potential uses include serving as second-line therapy in cases of recurrence or failed initial intervention or as neoadjuvant therapy to enhance the feasibility of resection. A notable concern arises regarding the possibility of tumour recurrence following the cessation of denosumab, with reported recurrence occurring months after treatment discontinuation. Hence, while denosumab demonstrates promising efficacy, it necessitates extended monitoring, particularly given that the follow-up duration in most cases in this review was limited to 2 years or less. Furthermore, rebound hypercalcemia upon discontinuation or tapering of denosumab therapy remains a concern, especially in paediatric patients, suggesting the need for prophylactic measures and consistent monitoring to mitigate this risk.

Moving forward, there is a need to gain deeper insights into the effectiveness and potential long-term side effects of denosumab in the treatment of ABC. While the prevalence of ABC is relatively low, which limits the immediate pool of patients for prospective trials, there remains a critical need to explore potential use of denosumab amongst ABC patients. Given the low prevalence of ABC, conducting a prospective clinical trial may present logistical challenges; however, the feasibility could be enhanced through multi-centre collaboration to pool patients across regions. In parallel, retrospective cohort studies utilizing existing clinical databases are a valuable strategy to gather more robust preliminary data, serving as a foundational step for future trial planning.

Footnotes

Declaration of conflicting interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iD

Vivek Ajit Singh

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