Hypophosphatemia after high-dose intravenous iron treatment in patients with inflammatory bowel disease: Mechanisms and possible clinical impact

Table 1 Descriptive data for laboratory parameters at baseline, at week 2 and at week 6

Analysis	High-dose intravenous iron	Baseline, mean ± SD	Week 2, mean ± SD	Difference from baseline at week 2	Difference between FCM and FDI at week 2 (95%CI)	P value	Week 6, mean ± SD	Difference from baseline at week 6	Difference between FCM and FDI at week 6 (95%CI)	P value
Serum phosphate, mmol/L (ref. value 0.8-1.65)	FCM	1.07 ± 0.2	0.65 ± 0.2	-0.417	-0.344 (-0.427 to -0.260)	< 0.001	1.00 ± 0.3	-0.072	-0.070 (-0.144 to 0.004)	0.064
	FDI	1.15 ± 0.2	1.07 ± 0.2	-0.073			1.14 ± 0.2	-0.002
Intact FGF23, pg/mL (ref. value 11.50-48.90)	FCM	43.42 ± 14.2	91.61 ± 63.8	49.205	45.312 (25.982 to 64.697)	< 0.001	44.79 ± 23.1	1.718	1.559 (-6.407 to 9.525)	0.698
	FDI	43.88 ± 14.5	47.77 ± 22.1	3.892			44.04 ± 16.6	0.159
C-terminal FGF23, pmol/L (ref. value 0.30-3.00)	FCM	2.46 ± 3.2	1.68 ± 1.3	-0.756	6.783 (-1.319 to 14.885)	0.099	0.94 ± 1.2	-1.507	5.124 (-1.310 to 11.558)	0.116
	FDI	8.87 ± 30.6	1.33 ± 1.4	-7.539			2.24 ± 7.6	-6.632
FEPO4, % (ref. value N/A)	FCM	9.95 ± 5.8	18.70 ± 10.8	9.946	5.375 (1.801 to 8.95)	0.004	13.68 ± 11.3	4.210	3.326 (-0.309 to 6.96)	0.072
	FDI	12.55 ± 5.9	17.03 ± 8.6	4.570			13.37 ± 6.0	0.884
PTH, pmol/L (ref. value 1.5-7.0)	FCM	5.46 ± 2.6	7.02 ± 3.4	1.608	0.442 (-0.561 to 1.445)	0.384	5.97 ± 3.3	0.767	0.590 (-0.358 to 1.539)	0.220
	FDI	5.51 ± 2.6	6.72 ± 3.4	1.166			5.69 ± 2.3	0.176
Ionised calcium, mmol/L (ref. value 1.16-1.32)	FCM	1.21 ± 0.0	1.20 ± 0.0	-0.015	-0.020 (-0.035 to -0.004)	0.012	1.21 ± 0.0	0.000	-0.018 (-0.036 to -0.001)	0.044
	FDI	1.23 ± 0.0	1.23 ± 0.1	0.005			1.25 ± 0.0	0.018
25-hydroxyvitamin D, nmol/L (ref. value 50-125)	FCM	58.35 ± 24.4	57.13 ± 23.1	-1.212	-2.133 (-6.238 to 1.972)	0.305	57.48 ± 20.8	-0.865	-0.160 (-7.078 to 6.759)	0.964
	FDI	63.51 ± 21.9	64.63 ± 20.0	0.922			62.75 ± 21.1	-0.706
1,25-dihydroxyvitamin D, ng/L (ref. value 20-79)	FCM	51.10 ± 19.2	28.77 ± 17.9	-21.074	-16.463 (-24.487 to -8.438)	< 0.001	53.78 ± 20.2	3.218	5.357 (-3.164 to 13.878)	0.215
	FDI	52.85 ± 20.4	48.24 ± 17.7	-4.611			50.71 ± 19.8	-2.139

Normal phosphate levels: > 0.8 mmol/L = > 2.48 mg/dL; Mild hypophosphatemia 0.79-0.6 mmol/L = 2.44-1.86 mg/dL; Moderate hypophosphatemia 0.59-0.32 mmol/L = 1.83-0.99 mg/dL; Severe hypophosphatemia < 0.32 mmol/L = < 0.99 mg/dL. CI: Confidence interval; FCM: Ferric carboxymaltose; FDI: Ferric derisomaltose; FEPO4: Fractional excretion of phosphate; FGF23: Fibroblast growth factor 23; PTH: Parathyroid hormone; N/A: Not applicable.

Table 2 Laboratory parameters for patients stratified by hypophosphatemia status (with/without) at week 2 and at week 6

Analysis	High-dose intravenous iron	Week 2 serum phosphate ≥ 0.8 mmol/L, mean ± SD	Week 2 serum phosphate < 0.8 mmol/L, mean ± SD	Difference	P value	Week 6 serum phosphate ≥ 0.8 mmol/L, mean ± SD	Week 6 serum phosphate < 0.8 mmol/L, mean ± SD	Difference	P value
Intact FGF23, pg/mL (ref. value 11.50-48.90)	FCM	33.71 ± 10.56 (n = 14/51)	114.33 ± 62.22 (n = 37/51)	80.62	< 0.001	39.30 ± 16.79) (n = 40/51)	66.86 ± 30.05 (n = 11/51)	27.56	0.013
	FDI	45.82 ± 16.90 (n = 47/53)	57.16 ± 46.35 (n = 6/53)	11.43	0.577	43.85 ± 16.83 (n = 52/54)	48.93 ± 10.13 (n = 2/54)	5.08	0.604
C-terminal FGF23, pmol/L (ref. value 0.30-3.00)	FCM	1.03 ± 0.99 (n = 14/51)	1.93 ± 1.33 (n = 37/51)	0.9	0.014	0.76 ± 0.63 (n = 40/51)	1.64 ± 2.14 (n = 11/51)	0.88	0.206
	FDI	1.36 ± 1.47 (n = 47/53)	1.08 ± 0.72 (n = 6/53)	-0.28	0.465	2.27 ± 7.79 (n = 52/54)	1.31 ± 0.33 (n = 2/54)	-0.97	0.384
FEPO4, % (ref. value N/A)	FCM	13.35 ± 5.94 (n = 12/46)	20.59 ± 11.60 (n = 34/46)	7.24	0.009	9.62 ± 6.56 (n = 36/47)	26.99 ± 13.38 (n = 11/47)	17.37	0.001
	FDI	15.97 ± 7.85 (n = 46/52)	25.11 ± 10.22 (n = 6/52)	9.14	0.080	13.00 ± 5.79 (n = 52/54)	22.85 ± 4.41 (n = 2/54)	9.85	0.176
PTH, pmol/L (ref. value 1.5-7.0)	FCM	5.46 ± 2.83 (n = 14/48)	7.46 ± 3.23 (n = 34/48)	2	0.042	5.22 ± 2.39 (n = 39/47)	9.93 ± 4.43) (n = 8/47)	4.71	0.020
	FDI	6.28 ± 2.97 (n = 47/53)	10.13 ± 4.70 (n = 6/53)	3.85	0.102	5.66 ± 2.32 (n = 52/54)	6.40 ± 1.70 (n = 2/54)	0.74	0.649
Ionised calcium, mmol/L (ref. value 1.16-1.32)	FCM	1.21 ± 0.32 (n = 13/50)	1.19 ± 0.05 (n = 37/50)	-0.02	0.336	1.21 ± 0.05 (n = 40/51)	1.22 ± 0.04 (n = 11/51)	0.01	0.496
	FDI	1.24 ± 0.45 (n = 46/52)	1.21 ± 0.09 (n = 6/52)	-0.03	0.422	1.25 ± 0.05 (n = 51/53)	1.23 ± 0.02 (n = 2/53)	-0.02	0.314
25-hydroxyvitamin D, nmol/L (ref. value 50-125)	FCM	63.00 ± 30.94 (n = 14/51)	54.54 ± 19.69 (n = 37/51)	-8.46	0.354	60.05 ± 21.68 (n = 40/51)	45.45 ± 10.00 (n = 11/51)	-14.6	0.002
	FDI	64.16 ± 20.30 (n = 45/51)	64.83 ± 18.93 (n = 6/51)	0.67	0.937	63.68 ± 20.97 (n = 50/52)	39.50 ± 2.12 (n = 2/52)	-24.18	< 0.001
1,25-dihydroxyvitamin D, ng/L (ref. value 20-79)	FCM	46.34 ± 19.10 (n = 14/50)	21.46 ± 11.63 (n = 36/50)	-24.88	< 0.001	56.76 ± 20.27 (n = 40/50)	40.89 ± 15.95 (n = 10/50)	-15.87	0.016
	FDI	49.05 ± 18.52 (n = 47/53)	45.72 ± 7.15 (n = 6/53)	-3.33	0.414	50.88 ± 19.92 (n = 52/54)	46.45 ± 21.85 (n = 2/54)	-4.43	0.822

Normal phosphate levels: > 0.8 mmol/L = > 2.48 mg/dL; Mild hypophosphatemia 0.79-0.6 mmol/L = 2.44-1.86 mg/dL; Moderate hypophosphatemia 0.59-0.32 mmol/L = 1.83-0.99 mg/dL; Severe hypophosphatemia < 0.32 mmol/L = < 0.99 mg/dL. FCM: Ferric carboxymaltose; FDI: Ferric derisomaltose; FEPO4: Fractional excretion of phosphate; FGF23: Fibroblast growth factor 23; PTH: Parathyroid hormone; N/A: Not applicable.

Table 3 Descriptive 36-item short form health survey scores for patient groups with/without hypophosphatemia independent of treatment group

SF-36 scale item	Normal phosphate population, baseline, mean ± SD	Hypophosphatemia population, baseline, mean ± SD	Difference1 at baseline, mean (95%CI)	Normal phosphate population, change at week 2, mean ± SD	Hypophosphatemia population, change at week 2, mean ± SD	Difference1 at week 2, mean (95%CI)	Normal phosphate population, change at week 6, mean ± SD	Hypophosphatemia population, change at week 6, mean ± SD	Difference1 at week 6, mean (95%CI)
General health	50.91 ± 20.1	48.50 ± 26.1	2.4 (-14.5 to 19.4)	-0.45 ± 12.9	0.75 ± 12.2	-1.2 (-9.2 to 6.8)	3.06 ± 16.3	3.25 ± 15.1	-0.2 (-10.2 to 9.8)
Physical functioning	78.72 ± 22.4	86.11 ± 21.1	-7.4 (-21.3 to 6.6)	2.63 ± 10.9	-0.28 ± 6.3	2.9 (-1.6 to 7.4)	3.97 ± 14.5	-0.28 ± 4.7	4.2 (0.2 to 8.3)
Role limitations due to physical problems	47.61 ± 42.8	66.67 ± 40.4	-19.1 (-45.7 to 7.6)	-4.08 ± 28.1	-6.25 ± 18.8	2.2 (-10.8 to 15.1)	11.32 ± 39.2	2.08 ± 16.7	9.2 (-3.7 to 22.1)
Bodily pain	65.65 ± 25.1	67.17 ± 27.6	-1.5 (-19.6 to 16.5)	0.68 ± 18.9	4.42 ± 12.2	-3.7 (-12.2 to 4.7)	3.40 ± 19.8	10.83 ± 19.1	-7.4 (-20.0 to 5.2)
Vitality	37.98 ± 22.0	40.00 ± 22.4	-2.0 (-16.7 to 12.7)	4.05 ± 13.1	7.50 ± 15.9	-3.4 (-13.8 to 6.9)	10.89 ± 18.0	12.92 ± 16.0	-2.0 (-12.7 to 8.6)
Mental health	71.72 ± 18.9	70.33 ± 16.9	1.4 (-9.9 to 12.6)	3.37 ± 9.0	4.33 ± 5.0	-1.0 (-4.5 to 2.6)	4.89 ± 13.2	1.67 ± 11.1	3.2 (-4.2 to 10.7)
Social functioning	68.35 ± 26.3	68.75 ± 30.4	-0.4 (-20.2 to 19.4)	3.86 ± 16.7	7.29 ± 13.5	-3.4 (-12.5 to 5.6)	8.70 ± 20.7	7.29 ± 15.5	1.4 (-9.1 to 11.9)
Role limitations due to emotional problems	67.91 ± 41.5	72.22 ± 42.2	-4.3 (-32.1 to 23.4)	-2.66 ± 34.8	-8.33 ± 37.9	5.7 (-19.1 to 30.5)	6.52 ± 38.0	-2.78 ± 26.4	9.3 (-8.8 to 27.4)

Hypophosphatemia defined as serum phosphate < 0.8 mmol/L (< 2.5 mg/dL).

¹Differences are normal phosphate group minus hypophosphatemia group. CI: Confidence interval; SF-36: 36-Item short form health survey.

Table 4 Descriptive visual analogue scale score for patient groups with/without hypophosphatemia independent of treatment group

VAS item	Normal phosphate group, baseline, mean ± SD	Hypophosphatemia group, baseline, mean ± SD	Difference1 at baseline, mean (95%CI)	P value	Normal phosphate group, change at week 2, mean ± SD	Hypophosphatemia group, change at week 2, mean ± SD	Difference1 at week 2, mean (95%CI)	P value	Normal phosphate group, change at week 6, mean ± SD	Hypophosphatemia group, change at week 6, mean ± SD	Difference1 at week 6, mean (95%CI)	P value
General weakness	43.54 ± 28.7	31.17 ± 30.5	12.4 (-7.6 to 32.4)	0.205	-4.98 ± 14.9	-1.50 ± 17.2	-3.5 (-14.7 to 7.7)	0.515	-10.64 ± 21.9)	-6.33 ± 25.7	-4.3 (-21.1 to 12.5)	0.589
Fatigue	37.53 ± 30.0	29.58 ± 30.1	7.9 (-11.8 to 27.7)	0.403	-3.31 ± 19.4	-1.33 ± 17.9	-2.0 (-13.9 to 9.9)	0.728	-8.93 ± 22.0	-5.17 ± 26.7	-3.8 (-21.2 to 13.6)	0.648
Joint pain	17.30 ± 23.3	8.25 ± 14.8	9.1 (-1.2 to 19.3)	0.081	0.32 ± 14.3	-3.09 ± 6.9	3.4 (-1.9 to 8.7)	0.197	2.17 ± 18.0	0.17 ± 7.4	2.0 (-3.8 to 7.8)	0..489
Joint stiffness	13.31 ± 22.3	1.42 ± 3.4	11.9 (6.9 to 16.8)	< 0.001	-0.57 ± 18.1	-0.64 (2.1)	0.1 (-3.9 to 4.0)	0.972	0.99 ± 17.7	1.75 ± 8.5	-0.8 (-7.1 to 5.6)	0.807
Muscle pain	15.35 ± 23.1	5.83 ± 14.5	9.5 (-0.5 to 19.6)	0.062	-1.71 ± 14.6	2.45 (8.9)	-4.2 (-10.7 to 2.3)	0.194	-0.50 ± 20.6	-0.17 ± 11.0	-0.3 (-8.3 to 7.6)	0.932
Bone and skeletal pain	7.24 ± 19.4	1.92 ± 6.6	5.3 (-0.3 to 10.9)	0.061	1.85 ± 20.2	2.64 (8.7)	-0.8 (-7.7 to 6.1)	0.817	3.42 ± 18.7	-1.67 ± 6.8	5.1 (-0.5 to 10.7)	0.076
Difficulties performing daily activities	34.38 ± 28.5	29.67 ± 29.7	4.7 (-14.8 to 24.2)	0.611	-3.80 ± 14.9	-2.17 (23.5)	-1.6 (-16.8 to 13.5)	0.819	-9.45 ± 20.0	-11.00 ± 24.8	1.6 (-14.6 to 17.7)	0.839

Hypophosphatemia defined as serum phosphate < 0.8 mmol/L (< 2.5 mg/dL).

¹Differences are normal phosphate group minus hypophosphatemia group. CI: Confidence interval; VAS: Visual analogue scale.