Rethinking the role of bisphosphonates after denosumab treatment in locally advanced or unresectable aneurysmal bone cysts: A meta-analysis

Table 1 Details in a published series of patients with aneurismal bone cyst treated with denosumab with or without bisphosphonates

Ref.	Age	Gender	Localization	Status	Pre-denosumab treatment	DT duration	Response to DT	Group	Outcome after DTS	RFS	REC	Follow-up
Ghermandi et al[49], 2016	42	Male	Spine	PD	SAE	9	CR IR	1	SD	20	0	20
Ghermandi et al[49], 2016	16	Male	Spine	PD	SAE	7	CR IR	1	SD	16	0	16
Ntalos et al[50], 2017	35	Female	Pelvis-sacrum	R	SAE SURG DT 60 mg	17	CR IR	1	SD	15	0	15
Kurucu et al[51], 2017	16	Male	mandible	R	ST IT	11	CR IR	1	SD	20	0	20
Kurucu et al[51], 2017	17	Female	Pelvis	P		14	CR IR	1	REC CLIN ST	3	1	3
Kurucu et al[51], 2017	5	Female	Spine	P		12	CR IR	1	SD	12	0	12
Kurucu et al[51], 2017	6	Male	Pelvis	P		9	CR IR	1	REC CLIN HYST negative SD	6	0	20
Kurucu et al[51], 2017	8	Male	Humerus	R	SURG	12	CR	1	SD	12	0	12
Kurucu et al[51], 2017	16	Female	Spine	P		12	CR IR	1	REC DRCH	17	1	21
Kurucu et al[51], 2017	10	Female	Spine	P		6	CR PIR	1	REC SURGERY	6	1	24
Patel et al[52], 2018	16	Male	Spine	R	ST	12	CR IR	1	SD	12	0	12
Palmerini et al[53], 2018, Evangelisti et al[54], 2024	16	Male	L5-S1	P	SAE 5	41	CR IR	1	SD	24	0	24
Palmerini et al[53], 2018, Evangelisti et al[54], 2024	42	Male	Spine C7	P	SURG SAE 2	26	CR IR	1	REC DRCH ongoing SD 24 mos.	15	1	103
Palmerini et al[53], 2018, Evangelisti et al[54], 2024	25	Male	Spine Th10	P	ND	36	CR IR	1	REC MSC SD 26 mos.	20	1	56
Palmerini et al[53], 2018, Evangelisti et al[54], 2024	19	Male	Spine L3-L4	P	ND	10	CR IR	1	SD	33	0	33
Palmerini et al[53], 2018	12	Male	Proximal ulna	P		8	CR PIR	1	SD	12	0	12
Raux et al[55], 2019	8	Male	Spine	P		12	CR IR	1	REC DRCH ongoing SD 12 mos.	10	1	10
Raux et al[55], 2019	7	Female	Femur	R	SURG	4	CR IR	1	SD	32	0	32
Dürr et al[56], 2019	6	Male	Sacrum	P		12	CR IR	1	SD	6	0	6
Dürr et al[56], 2019	15	Female	Distal radius	PD	SURG ST	6	CR IR	1	SD	36	0	36
Dürr et al[56], 2019	16	Female	Distal femur	P	SURG SAE	24	CR IR	1	SD	24	0	24
Dürr et al[56], 2019	30	Female	Pelvis	R	SURG DT SURG	8	CR IR	1	REC DRCH ongoing SD	36	1	18
Dürr et al[56], 2019	18	Male	Sacrum	R	ST SAE	24	ND	1	REC DRCH ongoing SD 18 mos.	12	1	12
Dürr et al[56], 2019	16	Female	Talus	R	SURG	12	SD	1	REC as Ganglioma	24	0	24
Sydlik et al[57], 2019	6	Male	Femur	P		24	CR IR	1	SD	12	0	12
Kotaka et al[58], 2023	38	Male	Spine L3	P		3	CR IR	1	REC DRCH ongoing SD 37	17	1	37
Vanderniet et al[59], 2023	13	Male	Spine	P		12	IR	1	SD	36	0	36
Vanderniet et al[59], 2023	12	Female	Spine	P	SURG SAE	8	IR	1	SD	6	0	6
Evangelisti et al[54], 2024	20	Male	Spine C6-C7	P	SURG SAE 1	12	CR IR	1	SD	43	0	43
Kulkarni et al[65], 2019	14	Female	Spine	R	SURG	6	CR IR	1	SD	24	0	24
Evangelisti et al[54], 2024	26	Female	Spine C4	P	MSC 1	17	CR IR	1	REC DRCH ongoing 20 mos.	10	1	43
Kurucu et al[51], 2017	12	Male	Pelvis	P		14	CR IR	2	SD	10	0	10
Kurucu et al[51], 2017	16	Male	Sacrum	R	SURG	14	CR PIR	2	SD	12	0	12
Upfill-Brown et al[60], 2019	10	Female	Pelvis	R	SURG	11	CR IR	2	SD	13	0	13
Raux et al[55], 2019	8	Male	Spine	R	SURG SAE	17	CR IR	2	SD	6	0	6
Sydlik et al[57], 2019	11	Male	Sacrum	P		16	CR IR	2	SD	12	0	12
Harcus 2020[61],	13	Male	Proximal tibia	R	SURG n 3	27	CR	2	SD	16	0	16
Del Sindaco et al[62], 2021	8	Male	Spine	P		12	CR IR	2	REC 9 mos. DRCH DTS SD	15	0	15
Deodati et al[63], 2022	10	Male	Pelvis	P		10	ND	2	SD	19	0	19
Vanderniet et al[59], 2023	12	Male	Spine	P	SURG SAE ST	18	IR	2	SD	42	0	42
Vanderniet et al[59], 2023	10	Female	Spine	P		18	IR	2	SD	24	0	24
Vanderniet et al[59], 2023	13	Male	Spine	P	SURG SAE ST	12	IR	2	SD	12	0	12
Gandolfi et al[64], 2023	10	Female	Sacrum	R	SURG SAE	25	CR	2	SD	6	0	6

DT: Denosumab treatment; DTS: Denosumab treatment stopping; RFS: Recurrence-free survival time; REC: Recurrence; 0: No, 1: Yes; PD: Progressive disease; P: Primary tumor; R: Recurrent tumors; SAE: Selective arterial embolization; SURG: Surgery; IT: Immunotherapy; ST: Sclerotherapy; MSC: Mesenchymal cell therapy; CR: Clinical response; IR: Imaging response; PIR: Partial imaging response; ND: No data; SD: Stable disease; CLIN: Clinical recurrence; HYST: Histology; DRCH: Denosumab re-challenge.

Table 2 Demographics, tumor characteristics, treatment details and outcomes in two groups, n (%)/median (range)

Feature	Group 1 (n = 31)	Group 2 (n = 12)	P value
Gende			0.3
Male	18 (58)	9 (75)
Female	13 (42)	3 (25)
Age (years)	16 (5-42)	10.5 (8-16)	0.03
Site			0.2
Axial	23 (74)	11 (92)
Extremities	8 (26)	1 (8)
Primary/failed initial treatment/poor response	22 (71)	7 (58)	0.4
Recurrent	9 (29)	5 (42)
DT duration (months)	12 (4-41)	15 (10-27)	0.05
Clinical and/or imaging response to DT			0.9
Yes	27 (90)	10 (91)
No	3 (10)	1 (9)
Post-DT withdrawal follow-up (months)	16 (3-43)	12 (6-42)	0.4
Clinical and/or imaging and/or histological relapse			0.02
Yes	10 (32)	0 (0)
No	21 (68)	12 (100)

DT: Denosumab treatment.

Table 3 Side effects during and after denosumab therapy, n (%)

Side effects	Frequency
Hypercalcemia	12 (29)
Hypercalcemia + Growth plate ossification	1 (2)
Hypocalcemia + Hypercalcemia	1 (2)
Hypocalcemia + Hypophosphatemia + Hypercalcemia	1 (2)
Hypocalcemia + Hypophosphatemia	1 (2)
Vomiting	1 (2)
Not reported	26 (60)
Total	43

Table 4 Bisphosphonate therapy regimens of rebound hypercalcemia during and after denosumab treatment

Ref.	Age/gender	Site	BPs therapy	BPs therapy in months
Kurucu et al[51], 2017	12/Male	Pelvis	BPs 1 dose	1
Kuruku et al[51], 2017	16/Male	Sacrum	BPs 1 dose	1
Raux et al[55], 2019	8/Male	Spine	BPs 3 doses	6
Sydlik et al[57], 2019	11/Male	Sacrum	Neridronate 2 doses (2 mg/kg)	1
Upfill-Brown et al[60], 2019	10/Female	Pelvis	BPs 1 dose	1
Harcus et al[61], 2020	13/Male	PT	PAMI 2 IV doses (0.25 mg/kg and then 0.5 mg/kg, 24 hours apart). PAMI one IV dose (0.5 mg/kg). ZA one IV dose (0.05 mg/kg)	2
Del Sindaco et al[62], 2021	8/Male	Spine	ZA six IV doses (0.05 mg/kg)	6
Deodati et al[63], 2022			PAMI one IV dose (1 mg/kg) in 1 week. PAMI five IV doses every 15 days (0.5 mg/kg)	3
Vanderniet et al[59], 2023	12/Male	Spine	ZA two IV doses (0.025 mg/kg), oral risedronate up to 6 months	Up to 6
Vanderniet et al[59], 2023	10/Female	Spine	ZA two IV doses (0.025 mg/kg), oral risedronate up to 6 months	Up to 6
Vanderniet et al[59], 2023	13/Male	Spine	ZA one IV dose (0.025 mg/kg), oral risedronate up to 6 months	Up to 6
Gandolfi et al[64], 2023	10/Female	Sacrum	PAMI two IV doses (1 mg/kg). ZA one IV dose (0.03 mg/kg)	1

PAMI: Pamidronate IV infusion; ZA: Zoledronic acid IV infusion; PT: Proximal tibia; BP: Bisphosphonates.