Scientific opinion on the tolerable upper intake level for vitamin D, including the derivation of a conversion factor for calcidiol monohydrate

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. 2023 Aug 8;21(8):e08145. doi: 10.2903/j.efsa.2023.8145

Reference Study Country Duration Funding	Design	Subject characteristics at baseline ^(a)	Intervention ^(a)	Endpoint assessed	Results ^(a)	RoB Tier
Bischoff‐Ferrari et al. (2012) Switzerland Latitude [assumed] 47.4° N 4 mo Private funding	RCT (parallel) Inclusion criteria: White postmenopausal women aged 50–70, in general good health, with serum 25(OH)D level between 8–24 ng/mL [20–60 nmol/L], BMI 18–29 kg/m², and ability of giving informed consent. Exclusion criteria: Medical contraindications to vitamin D supplements, medical conditions, or medication use that would alter pharmacokinetics of study products or otherwise interfere with the study; specific exclusion criteria are listed in Appendix 1 that included e.g. current smokers; use of dietary supplements while on study, except multivitamins, must stop before entering the study and refrain from using until the end of the study; use of high‐dose vitamin D supplements >400 IU [>10 μg]; use of high‐dose calcium supplements >600 mg. N participants randomised/completed/analysed G1–G2: 10 October 2010 G3–G4: 10 October 2010	Sex: Females Age (y) G1–G2: 63.45 ± 7.78 G3–G4: 59.48 ± 6.27 Serum 25(OH)D (ng/mL) G1–G2: 14.18 ± 3.61 ng/mL [35.45 ± 9.03 nmol/L] G3–G4: 12.28 ± 4.08 ng/mL [30.70 ± 10.2 nmol/L] iPTH (pg/mL) G1–G2: 54.87 ± 10.71 G3–G4: 63.22 ± 16.37 BMI (kg/m²) G1–G2: 25.49 ± 3.38 G3–G4: 23.24 ± 3.22 Ethnicity: White Smoking status: Smokers were excluded Alcohol use: NR Health status: Healthy population. Season: NR	Doses G1: vitamin D₃ 20 μg/d G2: vitamin D₃ 140 μg/wk [=20 μg/d] G3: calcidiol 20 μg/d G4: calcidiol 140 μg/wk [=20 μg/d] The daily and weekly groups for each vitamin D form were combined for the analysis as the results between daily and weekly supplementations did not differ significantly. Background vitamin D intake: NR Background calcium intake: NR Compliance Pill count method: Complete adherence stated.	Serum 25(OH)D: measured by HPLC–MS/MS time of blood collection after last dosage: NR iPTH: measured by ECLIA	Data extracted: unclear Serum 25(OH)D at 4 mo (ng/mL), mean ± SE G1–G2: 30.99 ± 1.59 ng/mL [77.48 ± 3.98 nmol/L] G3–G4: 69.47 ± 1.58 ng/mL [173.68 ± 3.95 nmol/L] iPTH at 4 mo (pg/mL), mean ± SE G1–G2: 51.68 ± 3.43 G3–G4: 43.00 ± 3.43	1
Cashman et al. (2012) Republic of Ireland Latitude 51° N 10 wk Mixed funding	RCT (parallel) Inclusion criteria: White men and women aged 50 years or more. Exclusion criteria: If unwilling to discontinue the consumption of vitamin D–containing supplements 8 wk before the initiation of the study and throughout the study; if planning to take a winter vacation (during the course of the 10‐wk intervention) to a location at which either the altitude or the latitude was predicted to result in significant cutaneous vitamin D synthesis from solar radiation (eg, a winter sun coastal resort or a mountain ski resort); if using tanning facilities of any type; a severe medical illness, hypercalcaemia, known intestinal malabsorption syndrome, excessive alcohol use, use of medications known to interfere with vitamin D metabolism. N participants randomised/completed/analysed G1: 16/16/16 G2: 14/13/13 G3: 14/14/14 G4: 14/13/12	Sex (% females) G1: 63 G2: 62 G3: 50 G4: 42 Age (y) All: 57.2 ± 6.3 NR across groups. Serum 25(OH)D (nmol/L) G1: 42.7 ± 12.6 G2: 49.7 ± 16.2 G3: 42.5 ± 8.9 G4: 38.2 ± 9.9 Serum iPTH (ng/mL) G1: 65.6 (47.4–70.2) G2: 47.3 (41.5–57.5) G3: 58.6 (52.8–69.9) G4: 57.9 (42.5–73.5) BMI (kg/m²) All: 28.3 ± 4.8 NR across groups. Ethnicity: White Smoking status: NR Alcohol use: Excessive alcohol users were excluded. Health status: Apparently healthy population. Season: winter; 17–28th Jan to 21st Mar–8th Apr	Doses G1: placebo G2: vitamin D₃ 20 μg/d G3: calcidiol 7 μg/d G4: calcidiol 20 μg/d Background vitamin D intake (μg/d) G1: 6.5 (2.9–7.9) G2: 7.6 (2.9–5.4) G3: 5.1 (2.8–6.6) G4: 4.4 (3.7–6.1) Background calcium intake (mg/d) G1: 970 ± 503 G2: 1114 ± 494 G3: 1008 ± 415 G4: 794 ± 309 Compliance Pill count method (%) All: 97.0 (92.0–100). Stated to be similar across groups (P = 0.9).	Serum 25(OH)D: measured by ELISA (OCTEIA) Serum iPTH: measured by ELISA	Data extracted: PP Serum 25(OH)D at 5 wk/during intervention (nmol/L) G1: 39.7 ± 11.1 G2: 64.1 ± 9.5 G3: 60.8 ± 8.1 G4: 98.1 ± 20.5 Serum 25(OH)D at 10 wk (nmol/L) G1: 41.2 ± 11.1 G2: 69.0 ± 8.7 G3: 70.7 ± 9.9 G4: 134.6 ± 26.0 Serum iPTH at 10 wk (ng/mL) G1: 65.8 (54.5–87.8) G2: 44.2 (40.1–52.7) G3: 52.7 (41.1–62.7) G4: 40.5 (34.6–61.6)	1
Catalano et al. (2015) Italy Latitude [assumed] 38.2° N 24 wk Unclear funding	RCT (parallel) Inclusion criteria: Postmenopausal women; osteopenic in accordance with WHO criteria; without prevalent vertebral or nonvertebral fractures, and with a low fracture risk according to a validated fracture risk assessment tool; assuming a stabilized (at least 6 mo) HMG‐CoA reductase therapy with atorvastatin prescribed as appropriate at a dosage of 20 or 40 mg/day and if they showed serum 25(OH)D levels <30 ng/ mL [< 75 nmol/L]. Exclusion criteria: Cancer, liver or renal failure, hypo‐ or hypercalcaemia, and previous treatment with intravenous N‐BPs or previous (within 6 months) hormone replacement therapy or assumption of selective oestrogen receptor modulators. N participants randomised/completed/analysed G1: 28/NR/28 G2: 29/NR/29	Sex: Females Age (y) G1: 59.46 ± 6.12 G2: 58.62 ± 7.35 Serum 25(OH)D (ng/mL) G1: 20.35 ± 5.46 ng/mL [50.88 ± 13.65 nmol/L] G2: 22.30 ± 6.58 ng/mL [55.75 ± 16.45 nmol/L] Serum PTH: NR BMI (kg/m²) G1: 26.79 ± 2.45 G2: 27.48 ± 2.81 Ethnicity [assumed]: Majority Caucasian Smoking status (%) Current smoking: G1: 28 G2: 31 Alcohol use: NR Health status (%) Hypertension: G1: 28 G2: 34 Diabetes: G1: 36 G2: 44 Season: Enrolment period Sept to Dec 2012.	Doses G1: vitamin D₃ 140 μg/wk [=20 μg/d] G2: calcidiol 140 μg/wk [=20 μg/d] Background vitamin D intake: NR Background calcium intake: NR Compliance NR	Serum 25(OH)D: method of measurement NR time of blood collection after last dosage: NR Serum PTH: not measured	Data extracted: unclear Serum 25(OH)D at 24 wk (ng/mL) G1: 24.30 ± 7.82 ng/mL [60.75 ± 19.55 nmol/L] G2: 50.33 ± 15.45 ng/mL [125.83 ± 38.63 nmol/L] Serum PTH at 10 wk: NR	3
Corrado et al. (2021) Italy Latitude [assumed] 40.6° N 6 mo Unclear funding [stated no external funding received]	RCT (parallel) Inclusion criteria: Postmenopausal women with serum 25(OH)D level between 8 ng/mL to 24 ng/mL [20 to 60 nmol/L], BMI between 18 and 29 kg/m² and good health. Exclusion criteria: Taking drugs which could interfere with calcium and phosphate homeostasis; taking antihypertensive drugs, bisphosphonates, anticonvulsant, anticoagulant, corticosteroid, thiazide diuretics, hormone therapy, estrogen receptor modulators for 6 months prior to recruitment; diseases that can alter the vitamin D intestinal absorption; diseases with increased risk of hypercalcaemia (sarcoidosis, lymphoma, primary hyperparathyroidism), kidney stones, intestinal malabsorption (celiac disease, lactose intolerance, gastric resection), severe renal impairment, psychiatric disorder, motor disability; potentially unable to properly take the vitamin D supplementation and unable to perform muscular exercises; the occurrence of fractures in the last year or fall in the 3 mo before; high intensity exercise, abuse of alcohol, cigarettes, intensive sun exposure in the 3 mo before the study. N participants randomised/completed/analysed G1: 31/27/27 G2: 30/26/26	Sex: Females Age (y) G1: 63.4 ± 5.5 G2: 60.9 ± 8.1 Serum 25(OH)D (ng/mL) G1: 12.5 ± 2.46 [31.25 ± 6.15 nmol/L] G2: 13.3 ± 2.9 [33.25 ± 7.25 nmol/L] Serum PTH (units unclear) G1: 35.5 (4.1) G2: 28.3 (8.08) BMI (kg/m²) G1: 23.8 ± 1.5 G2: 23.3 ± 1.2 Ethnicity: White Smoking status: Cigarettes as an exclusion criterion. Alcohol use: Abusers of alcohol were excluded. Health status: Good health. Season: Oct to Apr.	Doses G1: vitamin D₃ 7000 IU/wk [175 μg/wk = 25 μg/d] G2: calcidiol 7000 IU/wk [175 μg/wk = 25 μg/d] The design also included two other groups treated with single dose of 300 000 IU [=7500 μg] of vitamin D₃ and monthly dose of 100 000 IU [=2500 μg] of vitamin D₃. The groups were ignored here as supplementation pattern was less frequent than weekly. Background vitamin D intake: NR Background calcium intake: NR Compliance NR	Serum 25(OH)D: measured by CLIA (Diasorin LIASON kit [accredited VDSP]) time of blood collection after last dosage: NR Serum PTH: measured by EIA	Data extracted: unclear Serum 25(OH)D₃ at 6 mo (nmol/L) G1: 50.9 ± 4.52 [127.25 ± 11.3 nmol/L] G2: 66.8 ± 3.98 [167.25 ± 9.95 nmol/L] Serum PTH at 6 mo (units unclear) G1: 34.2 (7.7) G2: 31.2 (6.7)	2
Graeff‐Armas et al. (2020) United Kingdom Latitude 51° N 6 mo Mixed funding	RCT (parallel) Inclusion criteria: Healthy Caucasian men and postmenopausal women aged >50 y, with a BMI of 20–32 kg/m² and willing to avoid direct sun exposure and restrict travel to sunny climates during the study period. Exclusion criteria: Taking vitamin D supplements (≤2 mo since last vitamin D supplement use), taking >500 mg/d of calcium from supplements; a history of hypercalcaemia, malabsorption, kidney or liver disease, acute or severe illness; planning a beach holiday, using a tanning bed, or heavy consumption of alcohol; being on steroids, anticonvulsants, antipsychotics, antibiotics, estrogen replacement, bisphosphonate, or recombinant PTH treatment or any drug that would alter gastrointestinal fat absorption. N participants randomised/completed/analysed G1: 22¹⁾/22/22 G2: 22¹⁾/20/21 G3: 23¹⁾/23/23 G4: 24¹⁾/23/24 ¹⁾ received intervention; two of the randomised participants did not receive treatment due to being unable to cannulate.	Sex (% females) G1: 59 G2: 64 G3: 61 G4: 50 Age (y) G1: 65.1 ± 9.3 G2: 62.8 ± 8.4 G3: 62.5 ± 6.8 G4: 63.0 ± 7.3 Serum 25(OH)D₃ (nmol/L) G1: 47.1 ± 15.0 (n = 21) G2: 48.0 ± 17.3 G3: 49.5 ± 17.2 G4: 48.5 ± 17.2 Serum iPTH (pmol/L) G1: 3.91 ± 1.28 G2: 4.12 ± 1.34 G3: 3.81 ± 1.11 G4: 3.99 ± 1.11 BMI (kg/m²) G1: 26.4 ± 3.1 G2: 26.1 ± 2.3 G3: 27.1 ± 3.1 G4: 25.4 ± 2.5 Ethnicity: Caucasian Smoking status: NR Alcohol use: Heavy alcohol users were excluded. Health status: Healthy Season: 12^th to 20^th Nov at baseline.	Doses [labeled] G1: vitamin D₃ 20 μg/d G2: calcidiol 10 μg/d G3: calcidiol 15 μg/d G4: calcidiol 20 μg/d Analysed doses G1: vitamin D₃ 20.8 μg/d G2: calcidiol 10.8 μg/d G3: calcidiol 15.6 μg/d G4: calcidiol 21.8 μg/d Background vitamin D intake (μg/d): NR Background calcium intake (mg/d): NR Compliance Pill count method (%) > 97 on average across groups and all visits.	Serum 25(OH)D₃: measured by LC–MS/MS Serum iPTH: measured by CLIA (Roche Cobas; Roche)	Data extracted: PP Serum 25(OH)D₃ at 6 mo (nmol/L) G1: 82.8 ± 18.1 (n = 21) G2: 103 ± 22.9 (n = 19) G3: 130 ± 20.5 G4: 153 ± 30.6 Serum iPTH at 6 mo (pmol/L) G1: 4.77 ± 1.86 G2: 4.31 ± 1.55 G3: 4.00 ± 0.98 G4: 4.00 ± 0.84 (n = 21)	1
Jakobsen et al. (2017) Denmark Latitude 55° N 3 x 6 wk Unclear funding	RCT (crossover) Inclusion criteria: Healthy, free‐living male adults aged 20 to 30 y. Exclusion criteria: BMI > 27 kg/m², had donated blood within the last 3 mo, any chronic diseases, use of medication regularly except for the occasional use of painkillers; were hypercalcemic, excessive consumption of alcohol, or known malabsorption syndromes. N participants randomised/completed/analysed G1: 12 December 2012 G2: 12 December 2012 G3: 12 December 2012	Sex: Males Age (y): 23 ± 3 Serum 25(OH)D (nmol/L): 56.1 ± 8.5 Serum iPTH (pmol/L): 3.2 ± 1.3 BMI (kg/m²): 23.2 ± 2 Ethnicity: Caucasian Smoking status: Non‐smokers Alcohol use: Excessive alcohol users were excluded. Health status: Healthy Season: Mid‐Oct 2006 to Mar 2007.	Doses G1: vitamin D₂ 10 μg/d G2: vitamin D₃ 10 μg/d G3: calcidiol 10 μg/d Analysed doses G1: vitamin D₂ 10.2 μg G2: vitamin D₃ 9.9 μg G3: calcidiol 9.8 μg Run‐in: vitamin D₃ 10 μg/d for 4 wk. Wash‐out: No Background vitamin D intake (μg/d): 1.1 ± 0.4 Measured 3 times during the intervention. Background calcium intake (mg/d): 806 ± 361 Measured 3 times during the intervention. Compliance Pill count method (%): 97	Serum 25(OH)D: measured by LC–MS/MS Serum iPTH: measured by CLIA	Data extracted: unclear Observed levels Serum 25(OH)D after 6 wk (nmol/L) G1: 44.2 ± 8.0 G2: 55.1 ± 8.9 G3: 64.7 ± 11.2 Serum iPTH after 6 wk (pmol/L) G1: 2.8 ± 1.0 G2: 2.1 ± 0.7 G3: 2.4 ± 0.9 Estimated levels, mean (95% CI) Serum 25(OH)D after 6 wk (nmol/L) G1: 43.5 (40.9, 46.4) G2: 54.4 (51.1, 58.0) G3: 63.8 (59.9, 67.9) Serum iPTH after 6 wk (pmol/L) G1: 2.6 (2.2, 3.0) G2: 2.0 (1.7, 2.4) G3: 2.2 (1.9, 2.6) Models included the factors treatment and period (P = 0.3–0.8), the covariate the baseline value, and a random effect of person.	2
Navarro‐Valverde et al. (2016) Spain Latitude 36.7° N 12 mo Unclear funding	RCT (parallel) Inclusion criteria: NR; was reported that post‐menopausal osteopenic women (diagnostic criteria NR) with good health, average age 67 years, and deficient in vitamin D (serum 25(OH)D 37.5 ± 5 nmol/L) were studied. Exclusion criteria: NR N participants randomised/completed/analysed G1: 10/NR/NR G2: 10/NR/NR G3: 10/NR/NR	Sex: Females Age (y) All: 67 ± 6 NR across groups. Serum 25(OH)D (nmol/L) G1: 40.5 ± 4.7 G2: 37.2 ± 4.2 G3: 38.0 ± 3.7 Serum PTH (ng/L) All: 57.2 ± 11.0 NR across groups. BMI (kg/m²) All: 26.4 ± 4 NR across groups. Ethnicity [assumed]: Majority Caucasian Smoking status: NR Alcohol use: NR Health status: Osteoporotic or osteopenic women? Former stated in abstract, latter stated in the methods; method of diagnosis NR Season: NR	Doses G1: vitamin D₃ 20 μg/d G2: calcidiol 20 μg/d G3: calcidiol 266 μg/wk [=38 μg/d] The design also included a group treated with fortnightly dose of 266 μg [=19 μg/d] of calcidiol. The group was ignored as supplementation pattern was less frequent than weekly. Background vitamin D intake: NR Background calcium intake: NR Compliance NR	Serum 25(OH)D: measured by HPLC and ultraviolet detection method time of blood collection after last dosage: NR Serum PTH: measured by ECLIA (Roche Diagnostic)	Data extracted: unclear Serum 25(OH)D at 6mo (nmol/L) G1: 80.0 ± 2.0 G2: 161 ± 21.7 G3: 213.5 ± 80.0 Serum 25(OH)D at 12 mo (nmol/L) G1: 86.2 ± 23.7 G2: 188.0 ± 24.0 G3: 233.0 ± 81.2 Serum 25(OH)D, change over 12 mo (nmol/L) G1: 45.7 ± 19.5 G2: 150.8 ± 22.3 G3: 195 ± 79.3 Serum PTH at 6 mo (ng/L) G1: 46.5 ± 11.2 G2: 38.7 ± 10.7 G3: 35.4 ± 8.4 Serum iPTH at 12 mo (ng/L) G1: 41.6 ± 10.5 G2: 32.5 ± 8.8 G3: 29.0 ± 5.9	3
Okoye et al. (2022) Italy Latitude [assumed] 43.7° N From hospital admission to 3 mo after discharge. Unclear funding [stated no external funding received]	RCT (parallel) Inclusion criteria: Geriatric patients consecutively hospitalized in the Geriatric Unit of the University Hospital of Pisa for acute illness, with 25(OH)D₃ levels <30 ng/mL [<75 nmol/L]. Exclusion criteria: Having received vitamin D supplementation during the past 6 mo; stage V renal insufficiency; liver failure (defined as a Child–Pugh classification of a B or C); hyperparathyroidism; malabsorption syndromes or the long‐term prescription of drugs reducing vitamin D absorption (i.e., antiepileptic drugs, long‐term corticosteroids, or bisphosphonates); neoplastic disease under treatment; patients being unable to give informed consent. N participants randomised/completed/analysed G1: 89/69/69 G2: 89/70/71	Sex (% females) G1: 56.5 G2: 59.1 Age (y): G1: 84.9 ± 6.4 G2: 82.7 ± 6.7 Plasma 25(OH)D₃ (ng/mL) G1: 16.8 ± 9.9 ng/mL [42.0 ± 24.75 nmol/L] G2: 18.8 ± 13.3 ng/mL [47.0 ± 33.25 nmol/L] PTH (ng/dL) G1: 48.1 ± 39.6 G2: 60.7 ± 36.9 BMI (kg/m²) G1: 23.7 (7.2) G2: 25.0 (5.6) Ethnicity [assumed]: Majority Caucasian Smoking status: NR Alcohol use: NR Health status (%) Arterial hypertension: G1: 69.6 G2: 70.4 Coronary heart disease: G1 11.6 G2: 9.9 Atrial fibrillation: G1: 17.4 G2: 19.7 Heart failure: G1: 42.0 G2: 39.4 Diabetes: G1: 20.3 G2: 21.1 Chronic kidney disease: G1: 23.2 G2: 22.5 Chronic obstructive pulmonary disease: G1: 8.6 G2: 9.8 Season: May to Sept 2020	Doses G1: vitamin D₃ 437.5 μg/wk [=62.5 μg/d] G2: calcidiol 140 μg/wk [=20 μg/d] Background vitamin D intake: NR Background calcium intake: NR Compliance Pill count method: Complete adherence stated.	Plasma 25(OH)D₃: measured by HPLC–MS/MS time of blood collection after last dosage: NR PTH: method of measurement NR	Data extracted: unclear Plasma 25(OH)D₃ at 3 mo (ng/mL) G1: 30.7 ± 8.4 ng/mL [76.75 ± 21.0 nmol/L] G2: 45.4 ± 9.8 ng/mL [113.5 ± 24.5 nmol/L] PTH at 3 mo (ng/dL): NR	3
Ruggiero et al. (2019) Italy Latitude [assumed] 43.1° N From hospital admission to 7 mo after discharge. Unclear funding [stated no external funding received]	RCT, pragmatic (parallel) Inclusion criteria: Community‐dwelling women and men, oldest‐old patients, aged >75 years, consecutively admitted to geriatric acute care ward. Exclusion criteria: On treatment with vitamin D, multivitamins, calcium supplements, anti‐fracture drugs or steroids; suffered from fragility fractures within 6 mo, cancer within 5 y, hyperparathyroidism, hypercalcaemia, hypercalciuria, hypophosphatemia, Paget's disease, chronic renal failure, nephrolithiasis, bowel inflammatory diseases, bowel resection, malabsorption syndrome, including celiac and Crohn's diseases, liver disease, excessive alcohol use, tuberculosis or sarcoidosis; major surgical within 6 mo, unable to walk outdoors before admission, were bedridden, nursing home residents at the time of admission or become eligible for nursing home placement during the course of the hospital stay, or if participating in other clinical studies. N participants randomised/completed/analysed G1: 33/NR/NR G2: 34/NR/NR	Sex (% females) G1: 61 G2: 65 Age (y) G1: 82.0 (77.0–86.0) G2: 83.5 (79.8–86.5) Serum 25(OH)D (ng/mL) G1: 10 (7–14) ng/mL [25 (17.5–35) nmol/L] G2: 10 (4–16) ng/mL [25 (10–40) nmol/L] Serum iPTH (pg/mL) G1: 50 (38–85) or 64.1 ± 38.2 G2: 104 (47–145) or 99.6 ± 51.2 BMI (kg/m²) G1: 27.5 (25.9–29.4) G2: 26.8 (24.4–28.6) Ethnicity[assumed]: Majority Caucasian Smoking status: NR Alcohol use: Excessive alcohol users were excluded. Health status: Number of comorbidities G1: 7 (5–10) G2: 7 (5–9) Season: NR	Doses G1: vitamin D₃ 150 μg/wk [=21.43 μg/d] G2: calcidiol 150 μg/wk [=21.43 μg/d] During hospital stay participants received 1000 mg/d calcium supplements; at discharge they received recommendations to assure adequate calcium intake from diet and, eventually, from supplements. Background vitamin D intake: NR Background calcium intake: NR Compliance Strategies to prove compliance were not implemented.	Serum 25(OH)D: measured by RIA (Diasorin) time of blood collection after last dosage: NR Serum iPTH: measured by EIA	Data extracted: unclear Serum 25(OH)D at 7 mo (ng/mL) G1: NR; increased by 16 ng/mL [40 nmol/L] on average G2: NR; increased by 19 ng/mL [47.5 nmol/L] on average. Serum iPTH (pg/mL) at 7 mo G1: 53.7 ± 13.6 G2: 58.9 ± 13.9	3
Shieh et al. (2017) USA Latitude [assumed] 34.05° N 16 wk Mixed funding	RCT (parallel) Inclusion criteria: Age ≥ 18 years and a baseline serum 25(OH)D level < 20 ng/mL [<50 nmol/L] Participants agreed to refrain from changing their dietary calcium intake and from taking self‐prescribed calcium or vitamin D supplements for the study duration. Exclusion criteria: History of hypercalcaemia, hypercalciuria, nephrolithiasis, intestinal malabsorption, or dysregulated vitamin D metabolism (from underlying comorbidity or medication). N participants randomised/completed/analysed G1: 16/NR/NR G2: 19/NR/NR	Sex: NR Age (y) G1: 36.9 ± 12.7 G2: 34.8 ± 8.6 Serum 25(OH)D (ng/mL) G1: 16.2 ± 3.7 [40.5 ± 9.25 nmol/L] G2: 17.0 ± 2.5 [42.5 ± 6.25 nmol/L] Serum iPTH (pg/mL) G1: 40.1 ± 18.6 G2: 34.6 ± 13.9 BMI (kg/m²) G1: 25.7 ± 6.1 G2: 27.4 ± 7.4 Ethnicity (%) White: G1: 12.5 G2: 15.8 African American: G1: 37.5 G2: 26.3 Asian American: G1: 37.5 G2: 31.6 Hispanic/Latino: G1: 12.5 G2: 26.3 Smoking status: NR Alcohol use: NR Health status: Healthy Season: NR	Doses G1: vitamin D₃ 60 μg/d G2: calcidiol 20 μg/d Background vitamin D intake: NR Background calcium intake: NR Compliance Pill count method (%) G1: 90.1 on average G2: 91.9 on average	Serum 25(OH)D: measured by CLIA (Diasorin LIAISON) Serum iPTH: measured by CLIA (Cobas; Roche)	Data extracted: unclear Serum 25(OH)D at 16 wk (ng/mL) G1: 29.6 ± 4.1 [74.0 ± 10.25 nmol/L] G2: 42.4 ± 15.9 [106.0 ± 39.75 nmol/L] Serum iPTH (pg/mL) at 16 wk: NR	1
Vaes et al. (2018a) the Netherlands Latitude 51° N 6 mo Mixed funding	RCT (parallel) Inclusion criteria: 65 years or older, with a serum 25(OH)D level between 20 and 50 nmol/L and a BMI between 18.5 and 35 kg/m²; prefrail or frail based on the frailty criteria of Fried et al (2001). Exclusion criteria: A serum calcium level >2.6 nmol/L or uncontrolled hypocalcemia, diagnosed malabsorption disorders, sarcoidosis, lymphoma, primary hyperparathyroidism, kidney stones (in the past 10 y), renal insufficiency, cancer, the use of medication that may influence vitamin D metabolism [e.g., bisphosphonates, parathyroid hormone (PTH) treatment, anti‐tuberculosis medications, anti‐epilepticmedications, bile acid sequestrate, or lipase inhibitors]; consumption of >21 servings of alcoholic beverages/wk; not willing or able to stop the use of vitamin D–containing supplements during the study; expected to increase their sun exposure (e.g., planned holiday), or had a surgery planned. N participants randomised/completed/analysed G1: 26/25/25 G2: 26/24/24 G3: 26/26/26	Sex (% females) G1: 46 G2: 42 G3: 46 Age (y) G1: 73.7 ± 6.2 G2: 74.8 ± 6.7 G3: 73.1 ± 6.0 Serum 25(OH)D (nmol/L), mean (95% CI) ²⁾ G1: 38.1 (32.5, 43.8) G2: 36.3 (30.6, 42.0) G3: 38.1 (32.5, 43.8) Plasma iPTH (pmol/L), mean (95% CI)²⁾ G1: 6.5 (5.6, 7.4) G2: 7.6 (6.7, 8.5) G3: 7.5 (6.6, 8.4) BMI (kg/m²) G1: 27.8 ± 3.7 G2: 27.4 ± 3.6 G3: 27.6 ± 3.5 Ethnicity[assumed]: Majority Caucasian Smoking status: NR Alcohol use: Those consuming >21 servings alcoholic beverages/wk were excluded. Health status (%) Prefrail: G1: 96 G2: 96 G3: 81 Frail: G1: 4 G2: 4 G3: 19 Season: Dec 2014 to Dec 2015. ²⁾ model‐adjustedmeans	Doses [labeled] G1: placebo G2: vitamin D₃ 20 μg/d G3: calcidiol 10 μg/d Analysed doses G1: placebo G2: vitamin D₃ 22.9 μg/d G3: calcidiol 9.9 μg/d Background vitamin D intake (μg/d) G1: 3.6 ± 1.5 G2: 3.6 ± 1.1 G3: 3.5 ± 1.6 Background calcium intake (mg/d) G1: 1010 ± 555 G2: 985 ± 304 G3: 1110 ± 481 Compliance Pill count method (%) All: 98 on average.	Serum 25(OH)D: measured by LC–MS/MS (The Vitamin D external quality certified laboratory) Plasma iPTH: measured by sandwich CLIA	Data extracted: ITT? Stated that analyses were performed on the basis of the intention‐to‐treat principle. Serum 25(OH)D at 6 mo (nmol/L), mean (95% CI) G1: 47.5 (41.8, 53.3) G2: 72.0 (66.1, 77.8) G3: 98.7 (93.1, 104.4) Serum 25(OH)D, change over 3 mo (nmol/L), mean (95% CI) ²⁾ G1: 9.6 (2.6, 16.5) G2: 31.8 (24.8, 38.9) G3: 54.0 (47.1, 60.8) Serum 25(OH)D, change over 6 mo (nmol/L), mean (95% CI) ²⁾ G1: 8.9 (2.0, 15.9) G2: 35.7 (28.6, 42.7) G3: 60.6 (53.7, 67.5) Plasma iPTH, change over 3 mo (pmol/L), mean (95% CI) ²⁾ G1: 0.1 (−0.7, 0.9) G2: −1.0 (−1.8, −0.2) G3: −2.0 (−2.8, −1.2) Plasma iPTH, change 6 mo (pmol/L), mean (95% CI) ²⁾ G1: 0.3 (−0.5, 1.1) G2: −1.4 (−2.2, −0.6) G3: −1.7 (−2.5, −0.9) ²⁾ model‐adjusted means; ”Covariates (age, sex, and BMI) were included on the basis of model fit”	1
Vaes et al. (2018b) the Netherlands Latitude 51° N 24 wk Private funding	RCT (parallel) Inclusion criteria: 65 years or older; a serum 25(OH)D₃ concentration between 25 and 50 nmol/L and a BMI between 20 and 35 kg/m². Exclusion criteria: A serum calcium level >2.6 mmol/L, diagnosis with kidney stones in the past 10 years, renal insufficiency, liver failure, malabsorption syndromes, sarcoidosis and primary hyperparathyroidism; use of medication that might interfere with vitamin D metabolism led to exclusion (e.g. thiazides, parathyroid hormone, bisphosphonates); consumed >3 alcoholic beverages per day, used vitamin D supplements in the 3 months prior to the screening visit, not willing to stop the use of multivitamins during the study, expected to increase sun exposure (e.g. planned holiday to a sunny resort), being blood donor or had a surgery planned. N participants randomised/completed/analysed G1: 14³⁾/12/11 G2: 14³⁾/13/12 G3: 15³⁾/15/14 G4: 16³⁾/14/14 ³⁾ received intervention; one of the randomised participants did not receive treatment due to violation of eligibility criteria.	Sex (% females) G1: 64 G2: 43 G3: 40 G4: 44 Age (y) G1: 78 ± 7.7 G2: 80 ± 7.3 G3: 79 ± 7.0 G4: 80 ± 7.0 Serum 25(OH)D₃ (nmol/L) G1: 37.7 ± 7.0 G2: 43.4 ± 15.8 G3: 38.3 ± 10.5 G4: 38.6 ± 12.9 iPTH (pmol/L) G1: 5.2 ± 1.9 G2: 5.7 ± 1.7 G3: 4.9 ± 1.3 G4: 4.9 ± 1.8 BMI (kg/m²) G1: 27.6 ± 3.5 G2: 26.0 ± 4.4 G3: 26.6 ± 3.7 G4: 26.8 ± 3.9 Ethnicity [assumed]: Majority Caucasian Smoking status (%) Non‐smokers: G1: 43 G2: 36 G3: 40 G4: 31 Ex‐smokers: G1: 50 G2: 64 G3: 60 G4: 69 Current smokers: G1: 7 G2: 0 G3: 0 G4: 0 Alcohol use (%) Light: G1: 71 G2: 79 G3: 93 G4: 75 Moderate: G1: 29 G2: 21 G3: 7 G4: 25 Excessive: G1: 0 G2: 0 G3: 0 G4: 0 Health status: NR Season: 26th Aug 2013 to 30th Apr 2014.	Doses [labeled] G1: vitamin D₃ 20 μg/d G2: calcidiol 5 μg/d G3: calcidiol 10 μg/d G4: calcidiol 15 μg/d Analysed doses G1: vitamin D₃ 22.3 μg/d G2: calcidiol 5.1 μg/d G3: calcidiol 10.3 μg/d G4: calcidiol 15.3 μg/d Background vitamin D intake (μg/d) G1: 3.7 ± 1.2 G2: 4.2 ± 1.6 G3: 3.3 ± 1.3 G4: 3.5 ± 1.5 Background calcium intake (mg/d) G1: 985 ± 438 G2: 1204 ± 487 G3: 1041 ± 293 G4: 1111 ± 386 Compliance Pill count method (%) All: 97 on average.	Serum 25(OH)D₃: all samples were measured at the end of the study; measured by LC–MS/MS iPTH: measured by sandwich CLIA	Data extracted: PP Serum 25(OH)D₃ at 24 wk (nmol/L), mean (95% CI) ⁴⁾ G1: 71.6 (63.2, 80.0) G2: 52.2 (44.4, 60.2) G3: 88.7 (81.4, 96.1) G4: 109.9 (102.5, 117.2) iPTH at 24 wk (pmol/L), mean (95% CI) ⁴⁾ G1: 4.7 (4.1, 5.2) G2: 5.1 (4.6, 5.6) G3: 4.8 (4.3, 5.3) G4: 3.9 (3.4, 4.4) ⁴⁾ model‐predicted means; ” The baseline level of the response variable and BMI were included as covariates in all models.”	1

Reference Study Country Duration Funding

Design

Subject characteristics at baseline ^(a)

Intervention ^(a)

Endpoint assessed

Results ^(a)

RoB Tier

Bischoff‐Ferrari et al. (2012)

Switzerland

Latitude [assumed] 47.4° N

4 mo

Private funding

RCT (parallel)

Inclusion criteria:

White postmenopausal women aged 50–70, in general good health, with serum 25(OH)D level between 8–24 ng/mL [20–60 nmol/L], BMI 18–29 kg/m², and ability of giving informed

consent.

Exclusion criteria:

Medical contraindications

to vitamin D supplements, medical conditions, or medication use that would alter pharmacokinetics of study products or otherwise interfere with the study; specific exclusion criteria are listed in Appendix 1 that included e.g. current smokers; use of dietary supplements while on study, except multivitamins, must stop before entering the study and refrain from using until the end of the study; use of high‐dose vitamin D supplements >400 IU [>10 μg]; use of high‐dose calcium supplements >600 mg.

N participants randomised/completed/analysed

G1–G2: 10 October 2010

G3–G4: 10 October 2010

Sex: Females

Age (y)

G1–G2: 63.45 ± 7.78

G3–G4: 59.48 ± 6.27

Serum 25(OH)D (ng/mL)

G1–G2: 14.18 ± 3.61 ng/mL [35.45 ± 9.03 nmol/L]

G3–G4: 12.28 ± 4.08 ng/mL [30.70 ± 10.2 nmol/L]

iPTH (pg/mL)

G1–G2: 54.87 ± 10.71

G3–G4: 63.22 ± 16.37

BMI (kg/m²)

G1–G2: 25.49 ± 3.38

G3–G4: 23.24 ± 3.22

Ethnicity: White

Smoking status:

Smokers were excluded

Alcohol use: NR

Health status:

Healthy population.

Season: NR

Doses

G1: vitamin D₃ 20 μg/d

G2: vitamin D₃ 140 μg/wk [=20 μg/d]

G3: calcidiol 20 μg/d

G4: calcidiol 140 μg/wk [=20 μg/d]

The daily and weekly groups for each vitamin D form were combined for the analysis as the results between daily and weekly supplementations did not differ significantly.

Background vitamin D intake: NR

Background calcium intake: NR

Compliance

Pill count method:

Complete adherence stated.

Serum 25(OH)D:

measured by HPLC–MS/MS

time of blood collection

after last dosage: NR

iPTH:

measured by ECLIA

Data extracted: unclear

Serum 25(OH)D at 4 mo (ng/mL), mean ± SE

G1–G2: 30.99 ± 1.59 ng/mL [77.48 ± 3.98 nmol/L]

G3–G4: 69.47 ± 1.58 ng/mL [173.68 ± 3.95 nmol/L]

iPTH at 4 mo (pg/mL), mean ± SE

G1–G2: 51.68 ± 3.43

G3–G4: 43.00 ± 3.43

Cashman et al. (2012)

Republic of Ireland

Latitude 51° N

10 wk

Mixed funding

RCT (parallel)

Inclusion criteria:

White men and women aged 50 years or more.

Exclusion criteria: If unwilling to discontinue the consumption of vitamin D–containing supplements 8 wk before the initiation of the study and throughout the study; if planning to take a winter vacation (during the course of the 10‐wk intervention) to a location at which either the altitude or the latitude was predicted to result in significant cutaneous vitamin D synthesis from solar radiation (eg, a winter sun coastal resort or a mountain ski resort); if using tanning facilities of any type; a severe medical illness, hypercalcaemia, known intestinal malabsorption syndrome, excessive alcohol use, use of medications known to interfere with vitamin D metabolism.

N participants randomised/completed/analysed

G1: 16/16/16

G2: 14/13/13

G3: 14/14/14

G4: 14/13/12

Sex (% females)

G1: 63

G2: 62

G3: 50

G4: 42

Age (y)

All: 57.2 ± 6.3

NR across groups.

Serum 25(OH)D (nmol/L)

G1: 42.7 ± 12.6

G2: 49.7 ± 16.2

G3: 42.5 ± 8.9

G4: 38.2 ± 9.9

Serum iPTH (ng/mL)

G1: 65.6 (47.4–70.2)

G2: 47.3 (41.5–57.5)

G3: 58.6 (52.8–69.9)

G4: 57.9 (42.5–73.5)

BMI (kg/m²)

All: 28.3 ± 4.8

NR across groups.

Ethnicity: White

Smoking status: NR

Alcohol use: Excessive alcohol users were excluded.

Health status:

Apparently healthy population.

Season:

winter; 17–28th Jan to 21st Mar–8th Apr

Doses

G1: placebo

G2: vitamin D₃ 20 μg/d

G3: calcidiol 7 μg/d

G4: calcidiol 20 μg/d

Background vitamin D intake (μg/d)

G1: 6.5 (2.9–7.9)

G2: 7.6 (2.9–5.4)

G3: 5.1 (2.8–6.6)

G4: 4.4 (3.7–6.1)

Background calcium intake (mg/d)

G1: 970 ± 503

G2: 1114 ± 494

G3: 1008 ± 415

G4: 794 ± 309

Compliance

Pill count method (%)

All: 97.0 (92.0–100).

Stated to be similar across groups (P = 0.9).

Serum 25(OH)D:

measured by ELISA (OCTEIA)

Serum iPTH:

measured by ELISA

Data extracted: PP

Serum 25(OH)D at 5 wk/during intervention (nmol/L)

G1: 39.7 ± 11.1

G2: 64.1 ± 9.5

G3: 60.8 ± 8.1

G4: 98.1 ± 20.5

Serum 25(OH)D at 10 wk (nmol/L)

G1: 41.2 ± 11.1

G2: 69.0 ± 8.7

G3: 70.7 ± 9.9

G4: 134.6 ± 26.0

Serum iPTH at 10 wk (ng/mL)

G1: 65.8 (54.5–87.8)

G2: 44.2 (40.1–52.7)

G3: 52.7 (41.1–62.7)

G4: 40.5 (34.6–61.6)

Catalano et al. (2015)

Italy

Latitude [assumed] 38.2° N

24 wk

Unclear funding

RCT (parallel)

Inclusion criteria:

Postmenopausal women; osteopenic in accordance with WHO criteria; without prevalent vertebral or nonvertebral fractures, and with a low

fracture risk according to a validated fracture risk assessment tool; assuming a stabilized (at least 6 mo) HMG‐CoA reductase therapy with

atorvastatin prescribed as appropriate at a dosage of 20 or 40 mg/day and if they showed serum 25(OH)D levels <30 ng/

mL [< 75 nmol/L].

Exclusion criteria:

Cancer, liver or renal failure, hypo‐ or hypercalcaemia, and previous treatment with intravenous N‐BPs or previous (within 6 months) hormone replacement therapy or assumption of selective oestrogen receptor modulators.

N participants randomised/completed/analysed

G1: 28/NR/28

G2: 29/NR/29

Sex: Females

Age (y)

G1: 59.46 ± 6.12

G2: 58.62 ± 7.35

Serum 25(OH)D (ng/mL)

G1: 20.35 ± 5.46 ng/mL [50.88 ± 13.65 nmol/L]

G2: 22.30 ± 6.58 ng/mL [55.75 ± 16.45 nmol/L]

Serum PTH: NR

BMI (kg/m²)

G1: 26.79 ± 2.45

G2: 27.48 ± 2.81

Ethnicity [assumed]: Majority Caucasian

Smoking status (%)

Current smoking:

G1: 28

G2: 31

Alcohol use: NR

Health status (%)

Hypertension:

G1: 28

G2: 34

Diabetes:

G1: 36

G2: 44

Season:

Enrolment period Sept to Dec 2012.

Doses

G1: vitamin D₃ 140 μg/wk [=20 μg/d]

G2: calcidiol 140 μg/wk [=20 μg/d]

Background vitamin D intake: NR

Background calcium intake: NR

Compliance

Serum 25(OH)D:

method of measurement NR

time of blood collection

after last dosage: NR

Serum PTH:

not measured

Data extracted: unclear

Serum 25(OH)D at 24 wk (ng/mL)

G1: 24.30 ± 7.82 ng/mL [60.75 ± 19.55 nmol/L]

G2: 50.33 ± 15.45 ng/mL [125.83 ± 38.63 nmol/L]

Serum PTH at 10 wk:

Corrado et al. (2021)

Italy

Latitude [assumed] 40.6° N

6 mo

Unclear funding [stated no external funding received]

RCT (parallel)

Inclusion criteria:

Postmenopausal women with serum 25(OH)D level between 8 ng/mL to 24 ng/mL [20 to 60 nmol/L], BMI between 18 and 29 kg/m² and good health.

Exclusion criteria:

Taking drugs which could

interfere with calcium and phosphate homeostasis; taking antihypertensive drugs, bisphosphonates, anticonvulsant, anticoagulant, corticosteroid, thiazide diuretics, hormone therapy, estrogen

receptor modulators for 6 months prior to recruitment; diseases that can alter

the vitamin D intestinal absorption; diseases with increased risk of hypercalcaemia (sarcoidosis, lymphoma, primary hyperparathyroidism), kidney stones, intestinal malabsorption (celiac disease, lactose intolerance, gastric resection), severe renal impairment, psychiatric disorder, motor disability; potentially unable to properly take the vitamin D supplementation and unable to perform muscular exercises; the occurrence of fractures in the last year or fall in the 3 mo before; high intensity exercise, abuse of alcohol, cigarettes, intensive sun exposure in the 3 mo before the study.

N participants randomised/completed/analysed

G1: 31/27/27

G2: 30/26/26

Sex: Females

Age (y)

G1: 63.4 ± 5.5

G2: 60.9 ± 8.1

Serum 25(OH)D (ng/mL)

G1: 12.5 ± 2.46 [31.25 ± 6.15 nmol/L]

G2: 13.3 ± 2.9 [33.25 ± 7.25 nmol/L]

Serum PTH (units unclear)

G1: 35.5 (4.1)

G2: 28.3 (8.08)

BMI (kg/m²)

G1: 23.8 ± 1.5

G2: 23.3 ± 1.2

Ethnicity: White

Smoking status: Cigarettes as an exclusion criterion.

Alcohol use: Abusers of alcohol were excluded.

Health status: Good health.

Season: Oct to Apr.

Doses

G1: vitamin D₃ 7000 IU/wk [175 μg/wk = 25 μg/d]

G2: calcidiol 7000 IU/wk [175 μg/wk = 25 μg/d]

The design also included two other groups treated with single dose of 300 000 IU [=7500 μg] of vitamin D₃ and monthly dose of 100 000 IU [=2500 μg] of vitamin D₃. The groups were ignored here as supplementation pattern was less frequent than weekly.

Background vitamin D intake: NR

Background calcium intake: NR

Compliance

Serum 25(OH)D:

measured by CLIA (Diasorin LIASON kit [accredited VDSP])

time of blood collection

after last dosage: NR

Serum PTH:

measured by EIA

Data extracted: unclear

Serum 25(OH)D₃ at 6 mo (nmol/L)

G1: 50.9 ± 4.52 [127.25 ± 11.3 nmol/L]

G2: 66.8 ± 3.98 [167.25 ± 9.95 nmol/L]

Serum PTH at 6 mo (units unclear)

G1: 34.2 (7.7)

G2: 31.2 (6.7)

Graeff‐Armas et al. (2020)

United Kingdom

Latitude 51° N

6 mo

Mixed funding

RCT (parallel)

Inclusion criteria:

Healthy Caucasian men and postmenopausal women aged >50 y, with a BMI of 20–32 kg/m² and willing to avoid direct sun exposure and restrict travel to sunny climates during the study period.

Exclusion criteria:

Taking vitamin D supplements (≤2 mo since last vitamin D supplement use), taking >500 mg/d of calcium from supplements; a history of hypercalcaemia, malabsorption, kidney or liver disease, acute or severe illness; planning a beach holiday, using a tanning bed, or heavy consumption of alcohol; being on steroids, anticonvulsants,

antipsychotics, antibiotics, estrogen replacement, bisphosphonate, or

recombinant PTH treatment or any drug that would alter gastrointestinal fat absorption.

N participants randomised/completed/analysed

G1: 22¹⁾/22/22

G2: 22¹⁾/20/21

G3: 23¹⁾/23/23

G4: 24¹⁾/23/24

¹⁾ received intervention; two of the randomised participants did not receive treatment due to being unable to cannulate.

Sex (% females)

G1: 59

G2: 64

G3: 61

G4: 50

Age (y)

G1: 65.1 ± 9.3

G2: 62.8 ± 8.4

G3: 62.5 ± 6.8

G4: 63.0 ± 7.3

Serum 25(OH)D₃ (nmol/L)

G1: 47.1 ± 15.0 (n = 21)

G2: 48.0 ± 17.3

G3: 49.5 ± 17.2

G4: 48.5 ± 17.2

Serum iPTH (pmol/L)

G1: 3.91 ± 1.28

G2: 4.12 ± 1.34

G3: 3.81 ± 1.11

G4: 3.99 ± 1.11

BMI (kg/m²)

G1: 26.4 ± 3.1

G2: 26.1 ± 2.3

G3: 27.1 ± 3.1

G4: 25.4 ± 2.5

Ethnicity: Caucasian

Smoking status: NR

Alcohol use: Heavy alcohol users were excluded.

Health status: Healthy

Season:

12^th to 20^th Nov at baseline.

Doses [labeled]

G1: vitamin D₃ 20 μg/d

G2: calcidiol 10 μg/d

G3: calcidiol 15 μg/d

G4: calcidiol 20 μg/d

Analysed doses

G1: vitamin D₃ 20.8 μg/d

G2: calcidiol 10.8 μg/d

G3: calcidiol 15.6 μg/d

G4: calcidiol 21.8 μg/d

Background vitamin D intake (μg/d): NR

Background calcium intake (mg/d): NR

Compliance

Pill count method (%)

> 97 on average

across groups and all visits.

Serum 25(OH)D₃:

measured by LC–MS/MS

Serum iPTH:

measured by CLIA (Roche Cobas; Roche)

Data extracted: PP

Serum 25(OH)D₃ at 6 mo (nmol/L)

G1: 82.8 ± 18.1 (n = 21)

G2: 103 ± 22.9 (n = 19)

G3: 130 ± 20.5

G4: 153 ± 30.6

Serum iPTH at 6 mo (pmol/L)

G1: 4.77 ± 1.86

G2: 4.31 ± 1.55

G3: 4.00 ± 0.98

G4: 4.00 ± 0.84 (n = 21)

Jakobsen et al. (2017)

Denmark

Latitude 55° N

3 x 6 wk

Unclear funding

RCT (crossover)

Inclusion criteria:

Healthy, free‐living male adults aged 20 to 30 y.

Exclusion criteria:

BMI > 27 kg/m², had donated blood within the last 3 mo, any chronic diseases, use of medication regularly except for the occasional use of painkillers; were hypercalcemic, excessive consumption of alcohol, or known malabsorption syndromes.

N participants randomised/completed/analysed

G1: 12 December 2012

G2: 12 December 2012

G3: 12 December 2012

Sex: Males

Age (y):

23 ± 3

Serum 25(OH)D (nmol/L):

56.1 ± 8.5

Serum iPTH (pmol/L):

3.2 ± 1.3

BMI (kg/m²):

23.2 ± 2

Ethnicity: Caucasian

Smoking status:

Non‐smokers

Alcohol use: Excessive alcohol users were excluded.

Health status: Healthy

Season:

Mid‐Oct 2006 to Mar 2007.

Doses

G1: vitamin D₂ 10 μg/d

G2: vitamin D₃ 10 μg/d

G3: calcidiol 10 μg/d

Analysed doses

G1: vitamin D₂ 10.2 μg

G2: vitamin D₃ 9.9 μg

G3: calcidiol 9.8 μg

Run‐in: vitamin D₃ 10 μg/d for 4 wk.

Wash‐out: No

Background vitamin D intake (μg/d):

1.1 ± 0.4

Measured 3 times during the intervention.

Background calcium intake (mg/d):

806 ± 361

Measured 3 times during the intervention.

Compliance

Pill count method (%): 97

Serum 25(OH)D:

measured by LC–MS/MS

Serum iPTH:

measured by CLIA

Data extracted: unclear

Observed levels

Serum 25(OH)D after 6 wk (nmol/L)

G1: 44.2 ± 8.0

G2: 55.1 ± 8.9

G3: 64.7 ± 11.2

Serum iPTH after 6 wk (pmol/L)

G1: 2.8 ± 1.0

G2: 2.1 ± 0.7

G3: 2.4 ± 0.9

Estimated levels, mean (95% CI)

Serum 25(OH)D after 6 wk (nmol/L)

G1: 43.5 (40.9, 46.4)

G2: 54.4 (51.1, 58.0)

G3: 63.8 (59.9, 67.9)

Serum iPTH after 6 wk (pmol/L)

G1: 2.6 (2.2, 3.0)

G2: 2.0 (1.7, 2.4)

G3: 2.2 (1.9, 2.6)

Models included the factors treatment and period (P = 0.3–0.8), the covariate the baseline value, and a random effect of person.

Navarro‐Valverde et al. (2016)

Spain

Latitude 36.7° N

12 mo

Unclear funding

RCT (parallel)

Inclusion criteria:

NR; was reported that post‐menopausal osteopenic women (diagnostic criteria NR) with good health, average age 67 years, and deficient in vitamin D (serum 25(OH)D 37.5 ± 5 nmol/L) were studied.

Exclusion criteria: NR

N participants randomised/completed/analysed

G1: 10/NR/NR

G2: 10/NR/NR

G3: 10/NR/NR

Sex: Females

Age (y)

All: 67 ± 6

NR across groups.

Serum 25(OH)D (nmol/L)

G1: 40.5 ± 4.7

G2: 37.2 ± 4.2

G3: 38.0 ± 3.7

Serum PTH (ng/L)

All: 57.2 ± 11.0

NR across groups.

BMI (kg/m²)

All: 26.4 ± 4

NR across groups.

Ethnicity [assumed]: Majority Caucasian

Smoking status: NR

Alcohol use: NR

Health status:

Osteoporotic or osteopenic women? Former stated in abstract, latter stated in the methods; method of diagnosis NR

Season: NR

Doses

G1: vitamin D₃ 20 μg/d

G2: calcidiol 20 μg/d

G3: calcidiol 266 μg/wk [=38 μg/d]

The design also included a group treated with fortnightly dose of 266 μg [=19 μg/d] of calcidiol. The group was ignored as supplementation pattern was less frequent than weekly.

Background vitamin D intake: NR

Background calcium intake: NR

Compliance

Serum 25(OH)D:

measured by HPLC and ultraviolet detection method

time of blood collection

after last dosage: NR

Serum PTH:

measured by ECLIA (Roche Diagnostic)

Data extracted: unclear

Serum 25(OH)D at 6mo (nmol/L)

G1: 80.0 ± 2.0

G2: 161 ± 21.7

G3: 213.5 ± 80.0

Serum 25(OH)D at 12 mo (nmol/L)

G1: 86.2 ± 23.7

G2: 188.0 ± 24.0

G3: 233.0 ± 81.2

Serum 25(OH)D, change over 12 mo (nmol/L)

G1: 45.7 ± 19.5

G2: 150.8 ± 22.3

G3: 195 ± 79.3

Serum PTH at 6 mo (ng/L)

G1: 46.5 ± 11.2

G2: 38.7 ± 10.7

G3: 35.4 ± 8.4

Serum iPTH at 12 mo (ng/L)

G1: 41.6 ± 10.5

G2: 32.5 ± 8.8

G3: 29.0 ± 5.9

Okoye et al. (2022)

Italy

Latitude [assumed] 43.7° N

From hospital admission to 3 mo after discharge.

Unclear funding [stated no external funding received]

RCT (parallel)

Inclusion criteria:

Geriatric patients consecutively hospitalized in the Geriatric Unit of the University Hospital

of Pisa for acute illness, with 25(OH)D₃ levels <30 ng/mL [<75 nmol/L].

Exclusion criteria:

Having received vitamin D supplementation during the past 6 mo; stage V renal insufficiency; liver failure (defined as a Child–Pugh classification of a B or C); hyperparathyroidism; malabsorption syndromes or the long‐term prescription of drugs reducing vitamin D absorption (i.e., antiepileptic drugs, long‐term corticosteroids, or bisphosphonates); neoplastic disease under treatment; patients being unable to give informed consent.

N participants randomised/completed/analysed

G1: 89/69/69

G2: 89/70/71

Sex (% females)

G1: 56.5

G2: 59.1

Age (y):

G1: 84.9 ± 6.4

G2: 82.7 ± 6.7

Plasma 25(OH)D₃ (ng/mL)

G1: 16.8 ± 9.9 ng/mL [42.0 ± 24.75 nmol/L]

G2: 18.8 ± 13.3 ng/mL [47.0 ± 33.25 nmol/L]

PTH (ng/dL)

G1: 48.1 ± 39.6

G2: 60.7 ± 36.9

BMI (kg/m²)

G1: 23.7 (7.2)

G2: 25.0 (5.6)

Ethnicity [assumed]: Majority Caucasian

Smoking status: NR

Alcohol use: NR

Health status (%)

Arterial hypertension:

G1: 69.6

G2: 70.4

Coronary heart disease:

G1 11.6

G2: 9.9

Atrial fibrillation:

G1: 17.4

G2: 19.7

Heart failure:

G1: 42.0

G2: 39.4

Diabetes:

G1: 20.3

G2: 21.1

Chronic kidney disease:

G1: 23.2

G2: 22.5

Chronic obstructive pulmonary disease:

G1: 8.6

G2: 9.8

Season:

May to Sept 2020

Doses

G1: vitamin D₃ 437.5 μg/wk [=62.5 μg/d]

G2: calcidiol 140 μg/wk

[=20 μg/d]

Background vitamin D intake: NR

Background calcium intake: NR

Compliance

Pill count method:

Complete adherence stated.

Plasma 25(OH)D₃:

measured by HPLC–MS/MS

time of blood collection

after last dosage: NR

PTH:

method of measurement NR

Data extracted: unclear

Plasma 25(OH)D₃ at 3 mo (ng/mL)

G1: 30.7 ± 8.4 ng/mL [76.75 ± 21.0 nmol/L]

G2: 45.4 ± 9.8 ng/mL [113.5 ± 24.5 nmol/L]

PTH at 3 mo (ng/dL):

Ruggiero et al. (2019)

Italy

Latitude [assumed] 43.1° N

From hospital admission to 7 mo after discharge.

Unclear funding [stated no external funding received]

RCT, pragmatic (parallel)

Inclusion criteria:

Community‐dwelling women and

men, oldest‐old patients, aged >75 years, consecutively admitted to geriatric acute care ward.

Exclusion criteria:

On treatment with vitamin D, multivitamins, calcium supplements, anti‐fracture drugs or steroids; suffered from fragility fractures within 6 mo, cancer within 5 y, hyperparathyroidism, hypercalcaemia, hypercalciuria, hypophosphatemia, Paget's disease, chronic renal failure, nephrolithiasis, bowel inflammatory diseases, bowel resection, malabsorption syndrome, including celiac and Crohn's diseases, liver disease, excessive alcohol use, tuberculosis or sarcoidosis; major surgical within 6 mo, unable to walk outdoors before admission, were bedridden, nursing home residents at the time of admission or become eligible for nursing home placement during the course of the hospital stay, or if participating in other clinical studies.

N participants randomised/completed/analysed

G1: 33/NR/NR

G2: 34/NR/NR

Sex (% females)

G1: 61

G2: 65

Age (y)

G1: 82.0 (77.0–86.0)

G2: 83.5 (79.8–86.5)

Serum 25(OH)D (ng/mL)

G1: 10 (7–14) ng/mL [25 (17.5–35) nmol/L]

G2: 10 (4–16) ng/mL [25 (10–40) nmol/L]

Serum iPTH (pg/mL)

G1: 50 (38–85) or 64.1 ± 38.2

G2: 104 (47–145) or 99.6 ± 51.2

BMI (kg/m²)

G1: 27.5 (25.9–29.4)

G2: 26.8 (24.4–28.6)

Ethnicity[assumed]: Majority Caucasian

Smoking status: NR

Alcohol use: Excessive alcohol users were excluded.

Health status:

Number of comorbidities

G1: 7 (5–10)

G2: 7 (5–9)

Season: NR

Doses

G1: vitamin D₃ 150 μg/wk [=21.43 μg/d]

G2: calcidiol 150 μg/wk [=21.43 μg/d]

During hospital stay participants received 1000 mg/d calcium supplements; at discharge they received recommendations to assure adequate calcium intake from diet and, eventually, from supplements.

Background vitamin D intake: NR

Background calcium intake: NR

Compliance

Strategies to prove compliance were not implemented.

Serum 25(OH)D:

measured by RIA (Diasorin)

time of blood collection

after last dosage: NR

Serum iPTH:

measured by EIA

Data extracted: unclear

Serum 25(OH)D at 7 mo (ng/mL)

G1: NR; increased by 16 ng/mL [40 nmol/L] on average

G2: NR; increased by 19 ng/mL [47.5 nmol/L] on average.

Serum iPTH (pg/mL) at 7 mo

G1: 53.7 ± 13.6

G2: 58.9 ± 13.9

Shieh et al. (2017)

USA

Latitude [assumed] 34.05° N

16 wk

Mixed funding

RCT (parallel)

Inclusion criteria:

Age ≥ 18 years and a baseline serum 25(OH)D level < 20 ng/mL [<50 nmol/L]

Participants agreed to refrain from changing their dietary calcium intake and from taking self‐prescribed calcium or

vitamin D supplements for the study duration.

Exclusion criteria:

History of hypercalcaemia, hypercalciuria, nephrolithiasis, intestinal malabsorption, or dysregulated vitamin D metabolism (from underlying comorbidity or medication).

N participants randomised/completed/analysed

G1: 16/NR/NR

G2: 19/NR/NR

Sex: NR

Age (y)

G1: 36.9 ± 12.7

G2: 34.8 ± 8.6

Serum 25(OH)D (ng/mL)

G1: 16.2 ± 3.7 [40.5 ± 9.25 nmol/L]

G2: 17.0 ± 2.5 [42.5 ± 6.25 nmol/L]

Serum iPTH (pg/mL)

G1: 40.1 ± 18.6

G2: 34.6 ± 13.9

BMI (kg/m²)

G1: 25.7 ± 6.1

G2: 27.4 ± 7.4

Ethnicity (%)

White:

G1: 12.5

G2: 15.8

African American:

G1: 37.5

G2: 26.3

Asian American:

G1: 37.5

G2: 31.6

Hispanic/Latino:

G1: 12.5

G2: 26.3

Smoking status: NR

Alcohol use: NR

Health status: Healthy

Season: NR

Doses

G1: vitamin D₃ 60 μg/d

G2: calcidiol 20 μg/d

Background vitamin D intake: NR

Background calcium intake: NR

Compliance

Pill count method (%)

G1: 90.1 on average

G2: 91.9 on average

Serum 25(OH)D:

measured by CLIA (Diasorin LIAISON)

Serum iPTH:

measured by CLIA (Cobas; Roche)

Data extracted: unclear

Serum 25(OH)D at 16 wk (ng/mL)

G1: 29.6 ± 4.1 [74.0 ± 10.25 nmol/L]

G2: 42.4 ± 15.9 [106.0 ± 39.75 nmol/L]

Serum iPTH (pg/mL) at 16 wk:

Vaes et al. (2018a)

the Netherlands

Latitude 51° N

6 mo

Mixed funding

RCT (parallel)

Inclusion criteria:

65 years or older, with a serum 25(OH)D level between 20 and 50 nmol/L and a BMI between 18.5 and 35 kg/m²; prefrail or frail based on the frailty criteria of Fried et al (2001).

Exclusion criteria:

A serum calcium level >2.6 nmol/L or uncontrolled hypocalcemia, diagnosed malabsorption disorders, sarcoidosis, lymphoma, primary hyperparathyroidism, kidney stones (in the past 10 y), renal insufficiency, cancer, the use of medication that may influence vitamin D metabolism [e.g., bisphosphonates, parathyroid hormone (PTH) treatment,

anti‐tuberculosis medications, anti‐epilepticmedications, bile acid sequestrate, or lipase inhibitors]; consumption of >21 servings of alcoholic beverages/wk; not willing or able to stop the use of vitamin D–containing supplements

during the study; expected to increase their sun exposure (e.g., planned holiday), or had a surgery planned.

N participants randomised/completed/analysed

G1: 26/25/25

G2: 26/24/24

G3: 26/26/26

Sex (% females)

G1: 46

G2: 42

G3: 46

Age (y)

G1: 73.7 ± 6.2

G2: 74.8 ± 6.7

G3: 73.1 ± 6.0

Serum 25(OH)D (nmol/L), mean (95% CI) ²⁾

G1: 38.1 (32.5, 43.8)

G2: 36.3 (30.6, 42.0)

G3: 38.1 (32.5, 43.8)

Plasma iPTH (pmol/L), mean (95% CI)²⁾

G1: 6.5 (5.6, 7.4)

G2: 7.6 (6.7, 8.5)

G3: 7.5 (6.6, 8.4)

BMI (kg/m²)

G1: 27.8 ± 3.7

G2: 27.4 ± 3.6

G3: 27.6 ± 3.5

Ethnicity[assumed]: Majority Caucasian

Smoking status: NR

Alcohol use: Those consuming >21 servings alcoholic beverages/wk were excluded.

Health status (%)

Prefrail:

G1: 96

G2: 96

G3: 81

Frail:

G1: 4

G2: 4

G3: 19

Season:

Dec 2014 to Dec 2015.

²⁾ model‐adjustedmeans

Doses [labeled]

G1: placebo

G2: vitamin D₃ 20 μg/d

G3: calcidiol 10 μg/d

Analysed doses

G1: placebo

G2: vitamin D₃ 22.9 μg/d

G3: calcidiol 9.9 μg/d

Background vitamin D intake (μg/d)

G1: 3.6 ± 1.5

G2: 3.6 ± 1.1

G3: 3.5 ± 1.6

Background calcium intake (mg/d)

G1: 1010 ± 555

G2: 985 ± 304

G3: 1110 ± 481

Compliance

Pill count method (%)

All: 98 on average.

Serum 25(OH)D:

measured by LC–MS/MS (The Vitamin D external quality certified laboratory)

Plasma iPTH:

measured by sandwich CLIA

Data extracted: ITT?

Stated that analyses were performed on the basis of the intention‐to‐treat principle.

Serum 25(OH)D at 6 mo (nmol/L), mean (95% CI)

G1: 47.5 (41.8, 53.3)

G2: 72.0 (66.1, 77.8)

G3: 98.7 (93.1, 104.4)

Serum 25(OH)D, change over 3 mo (nmol/L), mean (95% CI) ²⁾

G1: 9.6 (2.6, 16.5)

G2: 31.8 (24.8, 38.9)

G3: 54.0 (47.1, 60.8)

Serum 25(OH)D, change over 6 mo (nmol/L), mean (95% CI) ²⁾

G1: 8.9 (2.0, 15.9)

G2: 35.7 (28.6, 42.7)

G3: 60.6 (53.7, 67.5)

Plasma iPTH, change over 3 mo (pmol/L), mean (95% CI) ²⁾

G1: 0.1 (−0.7, 0.9)

G2: −1.0 (−1.8, −0.2)

G3: −2.0 (−2.8, −1.2)

Plasma iPTH, change 6 mo (pmol/L), mean (95% CI) ²⁾

G1: 0.3 (−0.5, 1.1)

G2: −1.4 (−2.2, −0.6)

G3: −1.7 (−2.5, −0.9)

²⁾ model‐adjusted means;

”Covariates (age, sex, and BMI) were included on the basis of model fit”

Vaes et al. (2018b)

the Netherlands

Latitude 51° N

24 wk

Private funding

RCT (parallel)

Inclusion criteria:

65 years or older; a serum 25(OH)D₃ concentration between 25 and 50 nmol/L and a BMI between 20 and 35 kg/m².

Exclusion criteria:

A serum calcium level >2.6 mmol/L, diagnosis with kidney stones in the past 10 years, renal insufficiency, liver failure, malabsorption syndromes, sarcoidosis and primary hyperparathyroidism; use of medication that might interfere with vitamin D metabolism led to exclusion (e.g. thiazides, parathyroid hormone, bisphosphonates); consumed >3 alcoholic beverages per day, used vitamin D supplements in the 3 months prior to the screening visit, not willing to stop the use of multivitamins during the study, expected to increase sun exposure (e.g. planned holiday to a sunny resort), being blood donor or had a surgery planned.

N participants randomised/completed/analysed

G1: 14³⁾/12/11

G2: 14³⁾/13/12

G3: 15³⁾/15/14

G4: 16³⁾/14/14

³⁾ received intervention; one of the randomised participants did not receive treatment due to violation of eligibility criteria.

Sex (% females)

G1: 64

G2: 43

G3: 40

G4: 44

Age (y)

G1: 78 ± 7.7

G2: 80 ± 7.3

G3: 79 ± 7.0

G4: 80 ± 7.0

Serum 25(OH)D₃ (nmol/L)

G1: 37.7 ± 7.0

G2: 43.4 ± 15.8

G3: 38.3 ± 10.5

G4: 38.6 ± 12.9

iPTH (pmol/L)

G1: 5.2 ± 1.9

G2: 5.7 ± 1.7

G3: 4.9 ± 1.3

G4: 4.9 ± 1.8

BMI (kg/m²)

G1: 27.6 ± 3.5

G2: 26.0 ± 4.4

G3: 26.6 ± 3.7

G4: 26.8 ± 3.9

Ethnicity [assumed]: Majority Caucasian

Smoking status (%)

Non‐smokers:

G1: 43

G2: 36

G3: 40

G4: 31

Ex‐smokers:

G1: 50

G2: 64

G3: 60

G4: 69

Current smokers:

G1: 7

G2: 0

G3: 0

G4: 0

Alcohol use (%)

Light:

G1: 71

G2: 79

G3: 93

G4: 75

Moderate:

G1: 29

G2: 21

G3: 7

G4: 25

Excessive:

G1: 0

G2: 0

G3: 0

G4: 0

Health status: NR

Season:

26th Aug 2013 to 30th Apr 2014.

Doses [labeled]

G1: vitamin D₃ 20 μg/d

G2: calcidiol 5 μg/d

G3: calcidiol 10 μg/d

G4: calcidiol 15 μg/d

Analysed doses

G1: vitamin D₃ 22.3 μg/d

G2: calcidiol 5.1 μg/d

G3: calcidiol 10.3 μg/d

G4: calcidiol 15.3 μg/d

Background vitamin D intake (μg/d)

G1: 3.7 ± 1.2

G2: 4.2 ± 1.6

G3: 3.3 ± 1.3

G4: 3.5 ± 1.5

Background calcium intake (mg/d)

G1: 985 ± 438

G2: 1204 ± 487

G3: 1041 ± 293

G4: 1111 ± 386

Compliance

Pill count method (%)

All: 97 on average.

Serum 25(OH)D₃:

all samples were measured at the end of the study; measured by LC–MS/MS

iPTH:

measured by sandwich

CLIA

Data extracted: PP

Serum 25(OH)D₃ at 24 wk (nmol/L), mean (95% CI) ⁴⁾

G1: 71.6 (63.2, 80.0)

G2: 52.2 (44.4, 60.2)

G3: 88.7 (81.4, 96.1)

G4: 109.9 (102.5, 117.2)

iPTH at 24 wk (pmol/L), mean (95% CI) ⁴⁾

G1: 4.7 (4.1, 5.2)

G2: 5.1 (4.6, 5.6)

G3: 4.8 (4.3, 5.3)

G4: 3.9 (3.4, 4.4)

⁴⁾ model‐predicted means;

” The baseline level of

the response variable and BMI were included as covariates in all

models.”

Abbreviations: CI: confidence interval; CLIA: chemiluminescence immune assay; CT: controlled trial; ECLIA: electrochemiluminescence immune assay; EIA: enzyme immunoassay; ELISA: enzyme‐linked immunosorbent assay; G: group; HPLC–MS/MS: high‐performance liquid chromatography tandem mass spectrometry; iPTH: intact parathyroid hormone; ITT: intention‐to‐treat; LC–MS/MS: liquid chromatography tandem mass spectrometry; NR: not reported; PP: per‐protocol; PTH: parathyroid hormone; RCT: randomised controlled trial; RIA: radioimmunoassay; SE: standard error; 25(OH)D: 25‐hydroxyvitamin D.

^(a)

the values have been reported as mean ± standard deviation or median (inter quartile range) unless otherwise indicated; interquartile range = 25^th–75^th percentiles or the length between the percentiles.