Table 7.

Summary of results from studies comparing supplementation with cholecalciferol vs. calcifediol.

Authors/Country	Year	Number and Type of Participants	Study Design	Cholecalciferol/Calcifediol Dose	Duration	Summary of Results
Corrado et al. Italy [165]	2021	107 postmenopausal women (mean age 60.8 ± 6.5 y)	Open-label RCT	–cholecalciferol: 100,000 IU single dose or 100,000 IU/month or 7000 IU/week –calcifediol: 7000 IU/week	6 months	Weekly calcifediol and cholecalciferol induced a greater and faster increase of serum 25(OH)D vs. monthly or single-dose cholecalciferol administration; 25(OH)D increase was associated with improved lower limbs muscle function. Supplementation with calcifediol was more effective and faster vs. cholecalciferol in increasing 25(OH)D serum levels and was associated with a greater improvement of muscular function.
Ruggiero et al. Italy [166]	2019	67 community-dwelling women and men, aged >75 y	Open-label RCT	–calcifediol: 150 μg/week –cholecalciferol: 150 μg/week	7 months	Supplementation with calcifediol and cholecalciferol were associated with significant increasing serum levels of 25(OH)D and 1,25(OH)2D in oldest–old persons, with a steeper rise and faster recovery of acceptable iPTH levels for those on calcifediol; after adjustment for iPTH levels the differences disappeared. Both supplementations were associated with a decreasing trend of iPTH and CRP. Polypharmacy and low muscle strength weaken the recovery of adequate 25(OH)D serum levels.
Vaes et al. Netherlands [167]	2018	59 men and women aged >65 y	Double-blind RCT	–calcifediol: 5, 10 or 15 μg/day –cholecalciferol: 20 μg/day	24 weeks	Supplementation with 20 μg/day of cholecalciferol increased 25(OH)D3 concentrations towards 28 ng/mL within 16 weeks. Supplementation with 10 or 15 μg/day of calcifediol increased 25(OH)D3 levels >28 ng/mL/L in 8 and 4 weeks, respectively. Steady state was achieved from week 12 onwards with serum 25(OH)D3 levels stabilizing between 84 and 89 nmol/L (33.6 and 35.6 ng/mL) in the 10 μg/day calcifediol group. No cases of hypercalcemia occurred in any treatment during the study period.
Shieh et al. USA [168]	2017	35 aged ≥18 y with 25(OH)D <20 ng/mL, from a multiethnic cohort	Open-label RCT	–calcifediol: 20 μg/day –cholecalciferol: 60 μg/day	16 weeks	Significant higher and faster increment of total and free 25(OH)D with calcifediol vs. cholecaciferol (total: +25.5 vs. +13.8 ng/mL; free: +6.6 vs. +3.5 pg/mL). By 4 weeks, 87.5% of calcifediol treated participants had total 25(OH)D levels ≥30 ng/mL, vs. 23.1% of cholecalciferol treated participants. Conclusions: calcifediol increased total and free 25(OH)D levels more rapidly than cholecalciferol, regardless of race/ethnicity. Free and total 25(OH)D were similarly associated with change in PTH.
Bischoff-Ferrari et al. Switzerland [169]	2016	200 community-dwelling men and women (67%) aged ≥70 y with a prior fall; 58% were vitamin D deficient (<20 ng/mL) at baseline	Double-blind RCT	–Group 1: cholecalciferol 24,000 IU/month –Group 2: cholecalciferol 60,000 IU/month –Group 3: cholecalciferol 24,000 IU/month plus calcifediol 300 μg/month	12 months	Participants in Group 3 vs. Group 1 were significantly more likely to achieve 25(OH)D levels of at least 30 ng/mL. Lower extremity function did not differ among the treatment groups. The incidence of falls was higher for Groups 2 and 3 vs. Group 1.
Navarro-Valverde et al. Spain [170]	2016	40 post-menopausal women (in 4 groups), mean age 67 ± y, deficient in vitamin D [mean 25(OH)D <15 ng/mL]	Open-label RCT	–Group 1: cholecalciferol 20 μg/day –Group 2: calcifediol 20 μg/day –Group 3: calcifediol 0.266 μg/week –Group 4: calcifediol 0.266 μg/two weeks	12 months	Calcifediol was significantly faster and 3–6 times more potent to obtain serum levels of 25(OH)D in the medium to long term. The authors concluded that both metabolites are not equipotent and that the therapeutic prescription guidelines should consider the differences to avoid over-dosage of calcifediol.
Meyer et al. Switzerland [171]	2015	20 post-menopausal women, mean age 61.5 ± 7.2 y, 25(OH)D between 8 and 24 ng/mL [mean 25(OH)D 13.2 ng/mL]	Double-blind RCT	–calcifediol: 20 μg/day –cholecalciferol: 20 μg/day	4 months	Increase in 25(OH)D levels was significantly higher in the calcifediol group vs. cholecalciferol group (to a mean of 69.3 ± 9.5 ng/mL vs. 30.5 ± 5.0 ng/mL, respectively). Calcifediol vs. cholecalciferol improved gait speed by 18% among these young postmenopausal women, after adjustments for baseline gait speed, age, and BMI. Changes in 25(OH)D blood levels over time were significantly correlated with improvement in gait speed. No effect could be demonstrated for trunk sway.
Catalano et al. Italy [172]	2015	57 postmenopausal women at low risk of fracture, on atorvastatin treatment, mean age 59 ± 6.7 y, 25(OH)D <30 ng/mL [mean 25(OH)D 13.2 ng/mL]	Open-label RCT	–calcifediol: 140 μg/week –cholecalciferol: 140 μg/week	24 weeks	25(OH)D increased significantly in both groups with higher levels in participants receiving calcifediol vs. cholecalciferol. Only in the calcifediol group, a significant reduction of LDL-C and an increase of HDL-C were observed, after adjustment for age, and baseline BMI, 25(OH)D and lipid levels. The percent changes in 25(OH)D levels were significantly associated with the variations of LDL-C but not with HDL-C levels.
Jetter et al. Switzerland [173]	2014	35 healthy females aged 50–70 y, 25(OH)D between 8 and 24 ng/mL	Double-blind RCT	–calcifediol: 20 μg/day or 140 μg/week or both for 15 weeks or a single bolus of 140 μg –cholecalciferol: 20 μg/day or 140 μg/week or both for 15 weeks or a single bolus of 140 μg –calcifediol single bolus of 140 μg plus cholecalciferol single bolus of 140 μg	15 weeks or single bolus	All women in the daily and weekly calcifediol groups achieved 25(OH)D3 concentrations >30 ng/mL (mean, 16.8 days), but only 70% in the cholecalciferol daily or weekly groups reached this concentration (mean, 68.4 days). A single dose of 140 μg calcifediol led to 117% higher 25(OH)D3 AUC0-96h values than 140 μg vitamin D3, while the simultaneous intake of both did not further increase exposure. The authors concluded that calcifediol given daily, weekly, or as a single bolus is about 2–3 times more potent in increasing plasma 25(OH)D3 concentrations vs. cholecalciferol, and concentrations of 30 ng/mL were reached more rapidly with calcifediol.
Bischoff-Ferrari et al. Switzerland [174]	2012	20 healthy postmenopausal women, with a mean 25(OH)D level of 13.2 ± 3.9 ng/mL and a mean age of 61.5 ± 7.2 y	Double-blind RCT	–calcifediol: 20 μg/day –cholecalciferol: 20 μg/day	4 months	Mean 25(OH)D levels increased rapidly to 69.5 ng/mL in the calcifediol group and to 31.0 ng/mL with a slow increase in the cholecalciferol group. All analyses were adjusted for baseline measurement, age, and BMI. Therapy with calcifediol vs. cholecalciferol had a significant 2.8-fold increased odds of maintained or improved lower extremity function, and a 5.7-mmHg significant decrease in SBP. Both types of vitamin D contributed to a decrease in five out of seven markers of innate immunity, significantly more pronounced with calcifediol for eotaxin, IL-12, MCP-1, and MIP-1 beta. There were no cases of hypercalcemia at any time point.
Cashman et al. Ireland [175]	2012	56 healthy, free-living adults aged ≥50 y	Double-blind RCT	–calcifediol: 7 or 20 μg/day –cholecalciferol: 20 μg/day	10 weeks	The mean increases (per μg of vitamin D compound) in serum 25(OH)D concentrations were 0.96 ± 0.62, 4.02 ± 1.27, and 4.77 ± 1.04 nmol/L for 20 μg/day of cholecalciferol and 7- and 20 μg/day of calcifediol, respectively. A comparison of the 7- and 20-μg of calcifediol groups with the 20 μg of cholecalciferol group yielded conversion factors of 4.2 and 5, respectively. There was no effect on serum calcium concentrations and no incidence of hypercalcemia. The authors concluded that each μg of calcifediol was about 5 times more effective in raising serum 25(OH)D in older adults in winter than an equivalent amount of cholecalciferol.
Rossini et al. Italy [178]	2005	271 postmenopausal women with osteopenia or osteoporosis with hypovitaminosis D	Open-label RCT	–calcifediol: 100 μg/week –cholecalciferol: 20–22 μg/day	12 months	The compliance to the weekly calcifediol was over 90% and led to serum levels of 25(OH)D, similar to those obtained with daily cholecalciferol. The potency of calcifediol vs. cholecalciferol in increasing 25(OH)D was 1.66 fold, but the study aimed to evaluate compliance, not efficacy.
Barger-Lux et al. USA [176]	1998	116 healthy men with usual milk consumption of ≤0.47 L/day, mean age of 28 ± 4 y, mean serum 25(OH)D of 26.8 ± 10 ng/mL from January to April	Open-label RCT	–Cholecalciferol 25, 250 or 1250 μg/day –Calcifediol 10, 20 or 50 μg/day –Calcitriol 0.5, 1.0 or 2.0 μg/day	8 weeks (group 1) 4 weeks (group 2) 2 weeks (group 3)	In participants treated with cholecalciferol serum 25(OH)D increased by 11.6, 58.4, and 257.2 ng/mL for the three dosage groups, respectively. Treatment with calcifediol increased circulating 25(OH)D by 16, 30.4, and 82.4 ng/mL, respectively. Treatment with calcitriol increased circulating 1,25(OH)2D by 10, 46, and 60 pmol/L, respectively. Slopes calculated from these data allowed the following estimates of mean treatment effects for typical dosage units in healthy 70-kg adults: an 8-week course of cholecalciferol at 10 μg/day would raise serum 25(OH)D by 4.4 ng/mL and a 4-week course of calcifediol at 20 μg/day would raise serum 25(OH)D by 37.6 ng/mL (potency of calcifediol vs. cholecalciferol in increasing 25(OH)D was 3.3–3.5 fold at a low dose and 7–8 fold for the highest dose of both compounds).
Stamp et al. UK [177]	1977	200 participants	Clinical practice		5 years	Ten times more cholecalciferol/ergocalciferol than calcifediol was required to produce equivalent plasma 25(OH)D concentration. The authors conclude that these data indirectly measure the superior therapeutic potency of calcifediol and the possible usefulness in patients with reduced 25-hydroxylation of vitamin D, or reduced solar exposure. Limitations of this study include: inclusion of patients with metabolic bone diseases; lack of homogeneity among the groups; use of ergocalciferol and cholecalciferol interchangeably without separating the results obtained by each of them; differences in duration of treatments of the diverse compounds.

AUC0-96h: area under the concentration-time curve; BMI: body mass index; CRP: C reactive protein; IL: interleukin; iPTH: intact parathyroid hormone; HDL-C: high-density lipoprotein cholesterol; LDL-C: low-density lipoprotein cholesterol; MCP-1: monocyte chemotactic protein-1; MIP-1 beta: macrophage inflammatory protein-1 beta; RCT: randomized controlled trial; SBP: systolic blood pressure; y: years.