Incidence and predictors of hypocalcemia in end-stage renal disease patients on denosumab therapy: A systematic review and meta-analysis

Table 1 Study characteristics

Ref.	Study design	Study sample	Sample size		Denosumab route of administration	Denosumab dosage	Control drug and dosage	Outcomes	Follow-up duration
			Denosumab	Control
Bird et al[17], 2024	Observational retrospective cohort study	Dialysis-dependent Medicare postmenopausal female patients aged ≥ 65 years	1523	1281	Subcutaneous	60 mg (6 monthly)	Oral bisphosphonate (alendronate, risedronate, and ibandronate) 70 mg (weekly)	Severe hypocalcemia (albumin-corrected serum calcium levels < 1.88 mmol/L, primary hospital hypocalcemia diagnosis, or emergency department hypocalcemia diagnosis); Very severe hypocalcemia (serum calcium levels < 1.63 mmol/L or emergency care)	12 wk
Cowan et al[18], 2023	Observational retrospective cohort study	Adults aged > 65 years with a new drug prescription for oral bisphosphonate or denosumab on chronic dialysis or eGFR < 15 mL/min/1.73 m2	174	85	Subcutaneous	60 mg (6 monthly)	Oral bisphosphonate (etidronate, alendronate, and risedronate)	Mild hypocalcemia (albumin-corrected serum calcium or levels < 2.0 mmol/L or ionized calcium levels < 1.0 mmol/L) within 180 d of new oral bisphosphonate/denosumab prescription; Severe hypocalcemia (albumin-corrected serum calcium or levels < 1.8 mmol/L or ionized calcium levels < 0.9 mmol/L) within 180 d of new oral bisphosphonate/denosumab prescription	180 d
Chen et al[19], 2020	Observational single-center case series	Patients with ESRD with SHPT and low bone mass undergoing dialysis	21	21	Subcutaneous	60 mg (single dose)	Conventional treatment	Changes in calcium, phosphate, and ALP levels; Changes in CAC from baseline; Adverse events	6 mo
Iseri et al[23], 2019	Randomized controlled trial	Patients diagnosed with osteoporosis undergoing hemodialysis	22	24	Subcutaneous	60 mg (6 monthly)	IV alendronate 900 mg (every 4 wk for 1 year)	Changes from baseline to 12 mo in LSBMD, BMD at other sites; Changes from pretreatment to 12 mo in BTM; Changes in serum calcium and phosphate levels from day 0 to day 14; New fractures and adverse events	12 mo
Takami et al[20], 2017	Observational retrospective case-control study	Patients with low BMD (< 70% of the young adult mean) undergoing hemodialysis	17	20	Subcutaneous	60 mg (6 monthly)	No denosumab	Changes in phosphorus, calcium, whole PTH, total ALP, and albumin levels from baseline to 12 mo; Radius BMD	12 mo
Chen et al[21], 2015	Open-label clinical trial	Patients with SHPT and low bone mass undergoing dialysis	24	8	Subcutaneous	60 mg (single dose)	No denosumab	Parathyroid gland volume; BMD; Adverse outcomes; Changes in serum calcium, phosphate, ALP, and iPTH from baseline to study completion	24 wk
Chen et al[22], 2014	Open-label clinical trial	Patients with ESRD and severe SHPT undergoing dialysis	12	8	Subcutaneous	60 mg (single dose)	No denosumab	Changes in serum calcium, phosphorus, ALP, BMD, and iPTH levels	6 mo

ALP: Alkaline phosphatase; BMD: Bone mineral density; BTM: Bone turnover marker; CAC: Coronary artery calcification; eGFR: Estimated glomerular filtration rate; ESRD: End-stage renal disease; iPTH: Intact parathyroid hormone; IV: Intravenous; LSBMD: Lumbar spine bone mineral density; PTH: Parathyroid hormone; SHPT: Secondary hyperparathyroidism.

Table 2 Baseline characteristics

Characteristic	Subcategory	Bird et al[17], 2024	Cowan et al[18], 2023	Chen et al[19], 2020	Iseri et al[23], 2019	Takami et al[20], 2017	Chen et al[21], 2015	Chen et al[22], 2014
Sample size	Denosumab	1523	174	21	22	17	24	12
	Control	1281	85	21	24	20	8	8
Female/male	Denosumab	1523/0	141/33	18/3	9/13	0/17	19/5	5/7
	Control	1281/0	48/37	12/9	9/15	0/20	2/6	3/5
Age in yr	Denosumab	74.5 ± 6.6	79.2 ± 7.7	62.14 ± 2.50	71.3 ± 10.5	72.8 ± 9.5	58.38 ± 2.77	53.5 ± 3.8
	Control	73.8 ± 6.5	78.0 ± 7.3	54.76 ± 2.00	71.5 ± 9.3	71.2 ± 11.0	58.50 ± 2.38	N/A
Serum calcium in mg/dL	Denosumab	9.3 ± 0.5	9.48 ± 0.16	9.96 ± 0.20	9.2 ± 0.5	9.2 ± 0.5	10.08 ± 0.16	10.1 ± 0.4
	Control	9.2 ± 0.6	9.4 ± 0.19	9.73 ± 0.20	9.3 ± 0.3	9.0 ± 0.5	10.30 ± 0.37	10.1 ± 0.3
Serum phosphate in mg/dL	Denosumab	4.7 ± 1.0	14.353 ± 0.67	5.50 ± 0.32	4.9 ± 1.1	5.0 ± 1.3	5.68 ± 0.29	5.3 ± 0.3
	Control	4.7 ± 1.1	14.477 ± 0.65	5.69 ± 0.21	4.6 ± 1.2	4.8 ± 1.2	5.79 ± 0.34	6.0 ± 0.3
Serum 25(OH)D in ng/mL	Denosumab	N/A	29.22 ± 12.34	27.01 ± 2.29	22.5 ± 9.5	N/A	30.04 ± 3.08	N/A
	Control	N/A	31.18 ± 14.05	25.16 ± 2.54	18.0 ± 9.3	N/A	32.36 ± 5.68	N/A
iPTH in pg/mL	Denosumab	N/A	295 ± 319.9	1310.50 ± 108.40	127.5 ± 83.2	150.2 ± 137.02	1464.77 ± 93.17	1702.1 ± 181.9
	Control	N/A	345.5 ± 456.81	1044.74 ± 61.24	138.4 ± 88.6	165.33 ± 98.14	974.58 ± 53.76	1300.1 ± 132.1
ALP in IU/L	Denosumab	N/A	N/A	268.38 ± 30.43	244.6 ± 60.8	276 ± 129	331.67 ± 48.86	449.8 ± 94.2
	Control	N/A	N/A	119.86 ± 8.85	265.9 ± 145.0	270 ± 69	112.50 ± 12.37	330.1 ± 81.3
BMI in kg/m2, mean ± SD	Denosumab	N/A	N/A	N/A	20.5 ± 2.7	21.6 ± 2.3	53.77 ± 1.74	N/A
	Control	N/A	N/A	N/A	21.1 ± 5.3	20.8 ± 2.3	62.48 ± 3.27	N/A
Diabetes	Denosumab	N/A	111 (63.8)	3 (14.3)	9 (40.9)	9 (52.9)	N/A	N/A
	Control	N/A	40 (47.1)	2 (9.5)	11 (45.8)	11 (55.0)	N/A	N/A
Use of vitamin D analogue	Denosumab	946 (62.1)	54 (31.0)	N/A	20 (90.9)	N/A	N/A	12 (100)
	Control	850 (66.4)	23 (27.1)	N/A	19 (79.2)	N/A	N/A	8 (100)

Data are presented as n (%) or mean ± standard deviation. 25(OH)D: 25-hydroxyvitamin D; ALP: Alkaline phosphatase; BMI: Body mass index; iPTH: Intact parathyroid hormone; N/A: Not applicable.