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; method of measurement Endpoint at baseline ^(a) Assay of serum 25(OH)D	Results ^(a)	RoB Tier
Children and adolescents
Al‐Shaar et al. (2013) Lebanon Latitude [assumed] 33.9° N 1 yr Private funding Based on the same study as El‐Hajj Fuleihan et al. (2006) below but reported different outcomes and groups.	RCT (parallel) Inclusion criteria: Aged 10 to 17 y; healthy based on careful physical examination; absence of a history of any disorders or medications known to affect bone metabolism. Exclusion criteria: Renal disease, liver disease, chronic diarrhea, and gastric and bowel surgery; used high‐dose vitamins within 6 mo of study entry; used corticosteroid therapy, anti‐epileptic drugs, rifampicin, or cholestyramine. N participants randomised/completed/analysed Females: G1: 58/55/55 G2: 62/58/58 G3: 59/55/54 Males: G1: 61/56/56 G2: 59/56/55 G3: 64/60/60	Sex (% females) All: 49.3 Age (y) Females: G1: 13.60 (11.65–15.65) G2: 12.56 (11.07–14.75) G3: 13.08 (11.13–14.72) Males: G1: 12.9 (11.8–14.8) G2: 12.6 (11.2–14.6) G3: 12.9 (11.4–14.8) Serum 25(OH)D (ng/mL) Females: G1: 11.7 (8.7–11.7) ng/mL [29.3 (21.8–29.3) nmol/L] G2: 11.3 (8.7–15.6) ng/mL [28.3 (21.8–39.0) nmol/L] G3: 12.6 (10.0–18.7) ng/mL [31.5 (25.0–46.8) nmol/L] Males: G1: 16.0 (12.9–19.5) ng/mL [40.0 (32.3–48.8) nmol/L] G2: 15.2 (12.1–18.8) ng/mL [38.0 (30.3–47.0) nmol/L] G3: 15.5 (11.7–18.7) ng/mL [38.8 (29.3–46.8) nmol/L] BMI (kg/m²) Females: G1: 19.9 (17.2–21.8) G2: 20.2 (17.9–23.0) G3: 19.4 (17.5–21.9) Males: G1: 20.8 (17.0–25.4) G2: 19.8 (17.3–24.5) G3: 20.3 (17.6–23.5) Ethnicity [assumed]: Arab Smoking status: NA Alcohol use: NR Health status: Healthy. Season: Recruitment occurred between Dec 2001 and June 2002.	Vitamin D₃ Doses G1: placebo G2: vitamin D₃ 1400 IU/wk [35 μg/wk = 5 μg/d] G3: vitamin D₃ 14 000 IU/wk [350 μg/wk = 50 μg/d] Analysed doses: Stated that the vitamin D concentration in the 3 solutions was within 10% of that anticipated based on the label on the bottles and the dilution protocol. Background vitamin D intake: NR Background calcium intake (mg/d) Reported in the earlier publication on girls (El‐Hajj Fuleihan, 2006) G1: 672 ± 323 G2: 674 ± 364 G3: 686 ± 411 Compliance Pill count method (%) Reported in the earlier publication on girls (El‐Hajj Fuleihan, 2006) Serum 25(OH)D at 1 yr (ng/mL) G1: 16 ± 8 ng/mL [40 ± 20 nmol/L] G2: 17 ± 6 ng/mL [42.5 ± 15 nmol/L] G3: 38 ± 31 ng/mL [95 ± 77.5 nmol/L]	BMD; DXA. Also measured in hip structural analysis: Cross sectional area, outer diameter, section modulus, and buckling ratio. ** BMD at baseline (g/cm ² ) Females Narrow neck: G1: 0.99 ± 0.2 G2: 0.99 ± 0.2 G3: 0.97 ± 0.2 Shaft: G1: 1.38 ± 0.24 G2: 1.34 ± 0.24 G3: 1.35 ± 0.24 Intertrochanteric: G1: 0.94 ± 0.20 G2: 0.91 ± 0.15 G3: 0.89 ± 0.16 Males Narrow neck: G1: 1.01 (0.89–1.22) G2: 1.03 (0.88–1.17) G3: 0.99 (0.87–1.19) Shaft: G1: 1.38 (1.22–1.79) G2: 1.38 (1.11–1.68) G3: 1.36 (1.18–1.65) Intertrochanteric: G1: 1.05 ± 0.20 G2: 1.03 ± 0.20 G3: 1.03 ± 0.21 ** Assay of serum 25(OH)D: CPBA (Diasorin, Incstar, Saluggia, Italy)	Data extracted: unclear BMD, change over 1 yr (%), mean ± SE Females Narrow neck: G1: 5.25 ± 0.96 G2: 7.50 ± 0.92 G3: 6.12 ± 0.98 P = 0.72 for difference in change between groups. ⁴⁾ Shaft: G1: 8.32 ± 0.84 G2: 9.10 ± 0.85 G3: 8.15 ± 0.84 P = 0.70 for difference in change between groups.⁴⁾ Intertrochanteric: G1: 5.18 ± 0.91 G2: 8.10 ± 0.88 G3: 5.84 ± 0.92 P = 0.06 for difference in change between groups. ⁴⁾ ⁴⁾ adjusted for baseline height, percentage change in lean mass and height, sun exposure, physical activity, calcium intake, and menarcheal status. (Table 4 presents wrong group sizes) Males Narrow neck: G1: 6.86 ± 0.97 G2: 5.88 ± 1.01 G3: 6.02 ± 0.93 P = 0.74 for difference in change between groups. ⁵⁾ Shaft: G1: 8.04 ± 0.81 G2: 8.05 ± 0.79 G3: 8.37 ± 0.75 P = 0.94 for difference in change between groups. ⁵⁾ Intertrochanteric: G1: 5.69 ± 0.95 G2: 5.07 ± 0.99 G3: 5.07 ± 0.92 P = 0.87 for difference in change between groups. ⁵⁾ ⁵⁾ adjusted for percentage change in lean mass. Females & Males No significant differences in %‐changes in cross sectional area, outer diameter, section modulus, or buckling ratio were observed between the groups, apart from the following in girls at the narrow neck: Outer diameter, change over 1 yr (%), mean ± SE G1: 2.77 ± 0.50 G2: 0.80 ± 0.48 G3: 1.97 ± 0.51 P = 0.02 for difference in change between groups. ⁴⁾ Buckling ratio, change over 1 yr (%), mean ± SE G1: −1.98 ± 1.32 G2: −6.53 ± 1.26 G3: −4.16 ± 1.34 P = 0.049 for difference in change between groups. ⁴⁾	1 for females; 2 for males
El‐Hajj Fuleihan et al. (2006) Lebanon Latitude [assumed] 33.9° N 1 yr Private funding Based on the same study as Al‐Shaar et al. (2013) above but reported different outcomes and groups	RCT (parallel) Inclusion criteria: Children and adolescents aged 10 to 17 y; healthy based on careful physical examination and absence of a history of any disorders or medications known to affect bone metabolism. It was stated that in boys, there was no consistent positive effect of vitamin D supplementation on BMD or BMC, which was why the paper stated they reported the results mainly on girls. Exclusion criteria: Renal disease, liver disease, chronic diarrhea, and gastric and bowel surgery; used high‐dose vitamins within 6 mo of study entry; used corticosteroid therapy, anti‐epileptic drugs, rifampicin, or cholestyramine. N participants randomised/completed/analysed: All (girls) G1: 58/55/55 G2: 62/58/58 G3: 59/55/55 Premenarcheal G1: NR/NR/8 G2: NR/NR/12 G3: NR/NR/14	Sex: Females Premenarcheal (%) G1: 14.5 G2: 20.7 G3: 25.5 Age (y) All G1: 13.6 ± 2.1 G2: 13.0 ± 2.1 G3: 13.1 ± 2.2 Premenarcheal G1: 10.9 ± 0.6 G2: 10.6 ± 0.6 G3: 10.8 ± 1.1 Serum 25(OH)D (ng/mL) All G1: 14 ± 7 ng/mL [35 ± 17.5 nmol/L] G2: 14 ± 9 ng/mL [35 ± 22.5 nmol/L] G3: 14 ± 8 ng/mL [35 ± 20 nmol/L] Premenarcheal G1: 13 ± 7 ng/mL [32.5 ± 17.5 nmol/L] G2: 15 ± 6 ng/mL [37.5 ± 15 nmol/L] G3: 14 ± 5 ng/mL [35 ± 12.5 nmol/L] BMI: NR Ethnicity [assumed]: Arab Smoking status: NA Alcohol use: NR Health status: Healthy. Season: Recruitment occurred between Dec 2001 and June 2002.	Vitamin D₃ Doses G1: placebo G2: vitamin D₃ 1400 IU/wk [35 μg/wk = 5 μg/d] G3: vitamin D₃ 14 000 IU/wk [350 μg/wk = 50 μg/d] Analysed doses: Stated that the vitamin D concentration in the 3 solutions was within 10% of that anticipated based on the label on the bottles and the dilution protocol. Background vitamin D intake: NR Background calcium intake (mg/d) All G1: 672 ± 323 G2: 674 ± 364 G3: 686 ± 411 Premenarcheal G1: 805 ± 430 G2: 811 ± 383 G3: 816 ± 570 Compliance Pill count method (%) G1: 98 ± 3 G2: 98 ± 3 G3: 97 ± 3 Serum 25(OH)D at 1 yr (ng/mL) G1: 16 ± 8 ng/mL [40 ± 20 nmol/L] G2: 17 ± 6 ng/mL [42.5 ± 15 nmol/L] G3: 38 ± 31 ng/mL [95 ± 77.5 nmol/L]	BMD and BMC; DXA. ** BMD at baseline: NR BMC at baseline (g) All Total hip: G1: 24.3 ± 5.4 G2: 22.8 ± 5.5 G3: 22.6 ± 5.9 Lumbar spine: G1: 41.1 ± 12.0 G2: 37.6 ± 10.7 G3: 39.2 ± 12.9 Femoral neck: G1: 3.3 ± 0.7 G2: 3.3 ± 0.7 G3: 3.3 ± 0.7 One‐third radius: G1: 1.4 ± 0.2 G2: 1.3 ± 0.2 G3: 1.3 ± 0.3 Premenarcheal Total hip: G1: 17.2 ± 5.3 G2: 15.8 ± 4.2 G3: 17.0 ± 3.8 Lumbar spine: G1: 25.2 ± 6.4 G2: 25.0 ± 5.2 G3: 27.4 ± 6.3 Femoral neck: G1: 2.4 ± 0.7 G2: 2.5 ± 0.5 G3: 2.6 ± 0.5 One‐third radius: G1: 1.0 ± 0.0 G2: 1.0 ± 0.2 G3: 1.0 ± 0.2 ** Assay of serum 25(OH)D: CPBA (Diasorin, Incstar, Saluggia, Italy)	Data extracted: ITT Stated that the results of ITT analyses were identical with the results of PP analyses in view of the very high compliance and the fact that those who retuned for follow‐up visits and BMD measurements were all taking the study medications. All BMD, change over 1 yr (%) Total hip: G1: 2.4 ± 4.5 G2: 4.0 ± 4.6 G3: 5.7 ± 5.8 P = 0.003 for difference in change between groups. Lumbar spine: G1: 4.0 ± 4.6 G2: 5.0 ± 6.3 G3: 4.3 ± 5.4 P = 0.61 for difference in change between groups. Femoral neck: G1: 0.7 ± 4.9 G2: 0.03 ± 4.8 G3: 0.8 ± 5.4 P = 0.67 for difference in % change between groups. One‐third radius: NR BMC, change over 1 yr (%) Total hip: G1: 7.8 ± 7.7 G2: 11.2 ± 9.3 G3: 12.8 ± 10.5 P = 0.02 for difference in change between groups. Lumbar spine: G1: 10.8 ± 8.5 G2: 14.5 ± 12.0 G3: 12.9 ± 10.4 P = 0.20 for difference in change between groups. Femoral neck: G1: 3.9 ± 7.2 G2: 4.4 ± 7.8 G3: 5.2 ± 8.0 P = 0.70 for difference in change between groups. One‐third radius: NR Premenarcheal BMD, change over 1 yr (%) Total hip: G1: 7.4 ± 7.5 G2: 8.0 ± 4.4 G3: 12.3 ± 6.5 P = 0.11 for difference in change between groups. Lumbar spine: G1: 3.4 ± 7.0 G2: 3.2 ± 9.5 G3: 4.4 ± 7.7 P = 0.93 for difference in change between groups. Femoral neck: G1: 5.0 ± 3.2 G2: 2.7 ± 5.5 G3: 4.9 ± 5.2 P = 0.45 for difference in % change between groups. One‐third radius: NR BMC, change over 1 yr (%) Total hip: G1: 12.3 ± 12.4 G2: 18.4 ± 9.1 G3: 23.2 ± 11.0 P = 0.08 for difference in change between groups. Lumbar spine: G1: 12.0 ± 9.9 G2: 18.8 ± 13.0 G3: 17.2 ± 10.2 P = 0.40 for difference in change between groups. Femoral neck: G1: 7.4 ± 4.5 G2: 9.3 ± 9.3 G3: 11.4 ± 7.9 P = 0.50 for difference in change between groups. One‐third radius: NR Postmenarcheal Stated there were no difference in BMD or BMC among the three treatment groups. Data not shown.	1 for females; 2 for males
Adults
Burt et al. (2019) Canada Latitude [assumed] 51.05° N 3 y Private funding	RCT (parallel) Inclusion criteria: Healthy men and women aged 55–70 years; DXA lumbar spine and total hip areal BMD T score > −2.5 SD, serum 25(OH)D between 30–125 nmol/L, and normal serum calcium (2.10–2.55 mmol/L). Participants were requested to take no more than 200 IU [5 μg] per day of additional vitamin D (eg. a multivitamin supplement). Exclusion criteria: Serum25(OH)D < 30 nmol/L or > 125 nmol/L; serum calcium >2.55 mmol/L or <2.10 mmol/L; vitamin D supplement use >2000 IU/d [50 μg/d] for the past 6 mo; use of bone active medication within the last 2 y; disorders known to affect vitamin D metabolism such as sarcoidosis, renal failure, malabsorption disorders, kidney stone within the past 2 y, or regular use of tanning salons; DXA T score compatible with osteoporosis at the lumbar spine, total hip or femoral neck; and high 10‐year risk (≥20%) for osteoporotic fracture (as defined by the World Health Organization's Canadian FRAX calculator). N participants, randomised/completed/analysed G1: 109/100/105 G2: 100/94/97 G3: 102/93/101	Sex (% females) G1: 42.9 G2: 48.5 G3: 47.5 Age (y) G1: 62.2 ± 4.2 G2: 62.6 ± 4.3 G3: 61.9 ± 4.1 Years since menopause G1: 12.6 ± 5.9 G2: 11.7 ± 7.3 G3: 12.5 ± 5.6 Serum 25(OH)D (nmol/L) G1: 76.7 ± 21.0 G2: 81.3 ± 20.1 G3: 78.4 ± 18.4 BMI (kg/m²) G1: 27.7 ± 4.3 G2: 28.1 ± 5.0 G3: 27.1 ± 4.1 Ethnicity (%) Non‐Hispanic White: G1: 93.3 G2: 96.9 G3: 97.0 Non‐Hispanic Black: G1: 1.0 G2: 1.0 G3: 0 Asian: G1: 4.7 G2: 2.1 G3: 2.0 Hispanic: G1: 1.0 G2: 0 G3: 1.0 Smokers (%) G1: 1.9 G2: 0 G3: 4.0 Alcohol use: NR Health status: NR Season: Aug 2013 to Dec 2017.	Vitamin D₃ Doses G1: vitamin D₃ 400 IU/d [10 μg/d] G2: vitamin D₃ 4000 IU/d [100 μg/d] G3: vitamin D₃ 10 000 IU/d [250 μg/d] Participants not consuming the recommended dietary allowance of calcium (1200 mg/d) received calcium tablets as needed (≤600 mg/d) to approximate a total daily intake of 1200 mg. Background vitamin D intake: NR Background calcium intake: NR Compliance Pill count method – number of days of supplement administration vs total number of days (%) All: 99 on average, (range 81–100). Serum 25(OH)D at 36 mo (nmol/L) G1: 77.4 ± 17.9 G2: 132.2 ± 28.0 G3: 144.4 ± 40.4	BMD; DXA vBMD; HR‐pQCT. Failure load; HR‐pQCT. Also measured: Cortical porosity, trabecular number. ** BMD at baseline (g/cm ² ) Total hip: G1: 1.02 ± 0.14 G2: 1.04 ± 0.14 G3: 1.01 ± 0.14 vBMD at baseline (mg/cm ³ ) Total, Radius: G1: 324.9 ± 61.5 G2: 335.9 ± 65.3 G3: 329.7 ± 60.0 Total, Tibia: G1: 301.2 ± 58.3 G2: 314.1 ± 52.9 G3: 306.5 ± 52.6 Trabecular, Radius: G1: 163.1 ± 40.3 G2: 160.4 ± 39.9) G3: 155.9 ± 40.2 Trabecular, Tibia: G1: 176.4 ± 37.7 G2: 174.8 ± 35.2 G3: 171.9 ± 38.7 Cortical, Radius: G1: 887.6 ± 50.0 G2: 899.2 ± 51.3 G3: 904.0 ± 53.3 Cortical, Tibia: G1: 853.9 ± 61.5 G2: 868.6 ± 52.9 G3: 871.5 ± 59.0 Failure load at baseline Radius: G1: 2700.7 ± 1020.7 G2: 2580.1 ± 990.4 G3: 2556.5 ± 964.4 Tibia: G1: 7831.3 ± 2420.1 G2: 7660.6 ± 2001.2 G3: 7533.5 ± 2209.9 ** Assay of serum 25(OH)D: CLIA (DiaSorin Liaison XL system)	Data extracted: unclear BMD at 36 mo (g/cm ² ) Total hip: G1: 1.02 ± 0.14 G2: 1.03 ± 0.15 G3: 1.00 ± 0.14 BMD, at 36 mo (g/cm ² ), mean, 95% CI Total hip: G2 vs G1: 0.0007, −0.0064 to 0.0078 G3 vs G1: 0.0019, −0.0052 to 0.0090 P = 0.87 for group x time interaction. vBMD at 36 mo (mg/cm ³ ) Total, Radius: G1: 320.1 ± 61.1 G2: 328.6 ± 66.1 G3: 317.3 ± 61.7 Total, Tibia: G1: 299.1 ± 58.7 G2: 309.1 ± 54.8 G3: 301.5 ± 54.6 Trabecular, Radius: G1: 164.8 ± 42.5 G2: 161.5 ± 42.0 G3: 155.1 ± 40.1 Trabecular, Tibia: G1: 179.1 ± 40.3 G2: 178.3 ± 39.1 G3: 175.2 ± 40.8 Cortical, Radius: G1: 879.6 ± 51.0 G2: 886.3 ± 52.4 G3: 884.9 ± 54.2 Cortical, Tibia: G1: 848.1 ± 68.8 G2: 856.6 ± 62.9 G3: 853.7 ± 67.9 vBMD, change over 36 mo (mg/cm ³ ), mean, 95% CI Total, Radius G2 vs G1: −3.9, −6.5 to −1.3 G3 vs G1: −7.5, −10.1 to −5.0 P < 0.001 for group x time interaction. Total, Tibia G2 vs G1: −1.8, −3.7 to 0.1 G3 vs G1: −4.1, −6.0 to −2.2 P < 0.001 for group x time interaction. Trabecular, Radius G2 vs G1: −0.95, −2.6 to 0.7 G3 vs G1: −2.71, −4.3 to −1.1 P = 0.012 for group x time interaction. Trabecular, Tibia G2 vs G1: 0.20, −0.1 to 1.5 G3 vs G1: −1.1, −2.4 to 0.2 P = 0.127 for group x time interaction. Cortical, Radius G2 vs G1: −6.3, −11.1 to −1.5 G3 vs G1: −8.6, −13.3 to −3.8 P = 0.001 for group x time interaction. Cortical, Tibia G2 vs G1: −4.2, −9.8 to 1.2 G3 vs G1: −9.8, −14.8 to −4.0 P = 0.004 for group x time interaction. Failure load at 36 mo Radius: G1: 2694.8 ± 1022.7 G2: 2550.5 ± 994.3 G3: 2470.6 ± 1001.5 P = 0.12 for group x time interaction. Tibia: G1: 7785.2 ± 2443.7 G2: 7576.9 ± 2125.0 G3: 7413.0 ± 2265.1 P = 0.06 for group x time interaction.	1
Grimnes et al. (2012) Norway Latitude 69° N 1 yr Private funding	RCT (parallel) Inclusion criteria: Postmenopausal women aged 50–80 years old with a T‐score in total hip or lumbar spine (L2–4) ≤ −2.0. Exclusion criteria: Use of hormone replacement therapy or other therapy affecting bone remodeling during the last 12 months before enrolment; use of steroids, renal stone disease, systolic blood pressure > 175 mmHg or diastolic blood pressure > 105 mmHg, serum creatinine >110 μmol/l, suspected primary hyperparathyroidism (serum calcium >2.55 mmol/l, serum calcium >2.50 mmol/l combined with plasma PTH >5.0 pmol/l, or serum calcium >2.45 mmol/l combined with plasma PTH >7.0 pmol/l), or chronic disease like ischemic heart disease, diabetes, granulomatous disease, and cancer. N participants randomised/completed/analysed: G1: 148/140/ITT 148, PP 140 G2: 149/135/ITT 149, PP 135	Sex: Females Age (y) G1: 63.5 ± 6.8 G2: 62.9 ± 7.6 Serum 25(OH)D (nmol/L) G1: 71.2 ± 22.3 G2: 70.7 ± 23.0 BMI (kg/m²) G1: 24.6 ± 3.2 G2: 25.0 ± 3.4 Ethnicity [assumed]: Majority Caucasian Smoking status (%) Current smokers: G1: 38 G2: 37 Former smokers: G1: 39 G2: 40 Alcohol use: NR Health status (%) Asthma/COPD: G1: 10 G2: 6 Thyroid disease: G1: 9 G2: 13 Arthrosis: G1: 9 G2: 11 Other musculoskeletal disease: G1: 11 G2: 15 Hypertension: G1: 19 G2: 17 Hypercholesterolemia: G1: 11 G2: 12	Vitamin D₃ Doses G1: vitamin D₃ 800 IU/d [20 μg/d] + calcium 1000 mg/d G2: vitamin D₃ 40 000 IU/wk [5714 IU/d = 142.9 μg/d] + 800 IU/day [20 μg/d] = 6514.29 IU/d [162.9 μg/d] + calcium 1000 mg/d Background vitamin D intake (μg/d) G1: 8.1 ± 6.0 G2: 9.1 ± 6.2 Background calcium intake (mg/d) G1: 1044 ± 552 G2: 1062 ± 524 Compliance Pill count method (%) All (vitamin D): 97 All (calcium): 92. Stated no differences across groups. Serum 25(OH)D, change over 12 mo (nmol/L): G1: 18.0 ± 18.9 G2: 114.7 ± 34.6 PP population.	BMD; DXA. ** BMD at baseline (g/cm ² ) Total hip: G1: 0.791 ± 0.082 G2: 0.790 ± 0.073 Lumbar spine (L2‐L4): G1: 0.902 ± 0.079 G2: 0.901 ± 0.072 Femoral neck G1: 0.757 ± 0.079 G2: 0.758 ± 0.066 ** Assay of serum 25(OH)D: LC–MS/MS (In‐house, Hormone Laboratory, Haukeland University Hospital)	Data extracted: ITT BMD, change over 12 mo (%) Total hip: G1: 0.56 ± 1.70 G2: 0.31 ± 1.59 P = 0.20 for difference in change between groups. Lumbar spine (L2‐L4): G1: 0.32 ± 3.23 G2: 0.25 ± 3.19. P = 0.86 for difference in change between groups. Femoral neck: G1: 0.17 ± 1.87 G2: 0.03 ± 2.08 P = 0.53 for difference in change between groups.	1
Jorde et al. (2010) Norway Latitude 70° N 1 yr Mixed funding	RCT (parallel) Inclusion criteria: Males and females 21–70 y, with BMI 28.0–47.0 kg/m². Exclusion criteria: Diabetes or a history of coronary infarction, angina pectoris, stroke, renal stone disease, or sarcoidosis; serum calcium >2.55 mmol/L, males with serum creatinine >129 μmol/L and females with serum creatinine >104 μmol/L; use of bisphosphonates or oestrogen (for contraception or replacement); a weight loss of >10% of total body weight during the last 6 mo; use of anti‐depressant drugs or weight reducing drugs; participating in an organized weight loss program; pregnancy or lactating women; women planning to become pregnant in the next 12 mo or < 50 years without adequate contraception (contraceptive pills, implantable subdermal contraceptive rods, contraceptive dermal patches, injectable contraceptives, vaginal contraceptive rings, or intrauterine devices, with pearl index <1.0). N participants randomised/completed/analysed: G1: 142/105/105 G2: 132/97/97 G3: 147/110/110	Sex (% females) G1: 61.0 G2: 59.8 G3: 60.0 Postmenopausal (%) G1: 55% G2: 48% G3: 44% Age (y) G1: 50.8 ± 10.7 G2: 47.7 ± 11.6 G3: 47.3 ± 11.1 Serum 25(OH)D (nmol/L) G1: 60.1 ± 22.3 G2: 58.3 ± 21.2 G3: 61.3 ± 20.7 BMI (kg/m²) G1: 35.2 ± 3.9 G2: 33.7 ± 3.5 G3: 34.4 ± 3.9 Ethnicity [assumed]: Majority Caucasian Smokers (%) G1: 17.1 G2: 20.6 G3: 20.9 Alcohol use: NR Health status: Healthy overweight. Season: Recruitment occurred in Nov 2005 to October 2006.	Vitamin D₃ Doses G1: placebo + calcium 500 mg/d G2: vitamin D₃ 20 000 IU/wk [2857 IU/d = 71.4 μg/d] + calcium 500 mg/d G3: vitamin D₃ 40 000 IU [5714 IU/d = 142.9 μg/d] + calcium 500 mg/d Background vitamin D intake: NR Background calcium intake: NR Compliance Pill count method – vitamin D/placebo capsules (%) G1: 96 G2: 96 G3: 95 Pill count method – calcium tablets (%) G1: 83 G2: 84 G3: 82 Serum 25(OH)D at 1 yr (nmol/L) G1: 57.9 ± 20.4 G2: 99.7 ± 20.3 G3: 140.9 ± 34.7	BMD; DXA. ** BMD at baseline (g/cm²) Total hip: G1: 1.092 ± 0.130 G2: 1.067 ± 0.128 G3: 1.107 ± 0.133 Lumbar spine (L2‐L4): G1: 1.251 ± 0.170 G2: 1.235 ± 0.161 G3: 1.270 ± 0.155 ** Assay of serum 25(OH)D: RIA (DiaSorin)	Data extracted: PP BMD, change over 1 yr (g/cm ² ) Total hip G1: 0.009 ± 0.017 G2: 0.011 ± 0.014 G3: 0.008 ± 0.014 Lumbar spine (L2‐L4): G1: 0.007 ± 0.042 G2: 0.008 ± 0.039 G3: 0.008 ± 0.036 P=NS for all comparisons vs G1 (exact values NR).	1
Rahme et al. (2017) Lebanon Latitude [assumed] 33.9° N 1 yr Mixed funding	RCT (parallel) Inclusion criteria: Ambulatory elderly, aged ≥65 y; overweight (BMI >25 kg/m²), serum 25(OH)D between 10 and 30 ng/mL [25 and 75 nmol/L] at screening. Exclusion criteria: Prediabetes if on oral hypoglycemic drugs; diabetes (fasting plasma glucose ≥126 mg/dL or glycated haemoglobin ≥6.5%); severe chronic diseases, or major organ failure (severe heart failure [stage III or IV], liver failure and cirrhosis, kidney failure [estimated glomerular filtration rate < 30 mL/min], cancer, and autoimmune diseases); conditions or being on medications known to affect bone metabolism; osteomalacia, a history of kidney stones, fragility fractures, or a 10‐yr fracture risk for major osteoporotic fractures exceeding 10% based on Fracture Risk Assessment Tool Lebanon risk calculator at study entry. N participants randomised/completed/analysed: G1: 128/112/112 G2: 129/110/110	Sex (% females) G1: 53.6 G2: 57.3 Age (y) G1: 71.0 ± 4.7 G2: 71.2 ± 4.8 Serum 25(OH)D (ng/mL) G1: 20.0 ± 7 ng/mL [50.0 ± 17.5 nmol/L] G2: 20.9 ± 8.2 ng/mL [52.3 ± 20.5 nmol/L] BMI (kg/m²) G1: 29.7 ± 4.6 G2: 30.6 ± 4.4 Ethnicity [assumed]: Arab Smoking status: NR Alcohol use: NR Health status: Overweight Season: Screening occurred between Jan 2011 and July 2013; the study ended in July 2014.	Vitamin D₃ Doses (labeled) G1: placebo + vitamin D₃ 500 IU/d [12.5 μg/d] + calcium 1000 mg/d G2: vitamin D₃ 20 000 IU/wk [500 μg/wk] + vitamin D₃ 500 IU/d [12.5 μg/d] + calcium 1000 mg/d = vitamin D₃ 3357 IU/d [83.9 μg/d] + calcium 1000 mg/d Analysed vitamin D₃ doses: G1: 600 IU/d [15 μg/d] G2: 22 000 IU/wk + 600 IU/d [15 μg/d] = 3742.86 IU/d [93.6 μg/d] Background vitamin D intake: NR Background calcium intake (mg/d) G1: 453 ± 323 G2: 397 ± 257 Background calcium + vitamin D supplement use (%) G1: 11 ± 10 G2: 11 ± 10 Compliance Pill count method (%) All: >90 for both calcium and vitamin D pills, for both groups. Serum 25(OH)D at 12 mo (ng/mL) G1: 25.9 ± 6.9 ng/mL [64.8 ± 17.3 nmol/L] G2: 36.0 ± 9.7 ng/mL [90.0 ± 24.3 nmol/L]	BMD; DXA. ** BMD at baseline (g/cm ² ) Total hip: G1: 0.826 ± 0.119 G2: 0.824 ± 0.118 Lumbar spine: G1: 0.886 ± 0.154 G2: 0.890 ± 0.150 Femoral neck: G1: 0.676 ± 0.102 G2: 0.671 ± 0.101 ** Assay of serum 25(OH)D: LC–MS (Mayo Clinic, Rochester, MN, USA)	Data extracted: PP BMD at 12 mo (g/cm ² ) Total hip: G1: 0.831 ± 0.121 G2: 0.828 ± 0.118 Lumbar spine: G1: 0.901 ± 0.162 G2: 0.900 ± 0.145 Femoral neck: G1: 0.682 ± 0.100 G2: 0.675 ± 0.099 BMD, change over 12 mo (%) Total hip: G1: 0.50 ± 2.26 G2: 0.47 ± 2.22 P = 0.909 for difference in % change between groups. Lumbar spine: G1: 1.34 ± 3.42 G2: 1.65 ± 3.21 P = 0.512 for difference in % change between groups. Femoral neck: G1: 0.55 ± 3.78 G2: 0.66 ± 4.16 P = 0.833 for difference in % change between groups.	1
Smith et al. (2018) ViDOS USA Latitude 41° N 1 yr Mixed funding	RCT (parallel) Inclusion criteria: Caucasian and African American postmenopausal women aged 57 to 90 years; vitamin D insufficiency defined as serum 25(OH)D ≤ 50 nmol/L. Exclusion criteria: Any significant disease or medications affecting calcium and bone metabolism: significant health problems, cancer within the last 10 y (except skin), previous hip fracture, hemiplegia, uncontrolled type 1 and type 2 diabetes, active kidney stones or history of kidney stones more than twice in their lifetime, body mass index (BMI) greater than 45 kg/m², serum 25(OH)D below 12.5 nmol/L, and chronic medical conditions involving liver, kidney, alcoholism or rheumatoid arthritis. Use of fluoride, bisphosphonates for more than 3 mo, PTH or derivatives within the last 6 months, calcitonin, estrogen, corticosteroid therapy of more than 10 mg/d, drugs interfering with vitamin D metabolism, such as phenytoin or phenobarbital, and high‐dose thiazide therapy (>37.5 mg/d). N participants, randomised/completed/analysed Caucasian: G1: 21/18/19 G2: 20/16/18 G3: 21/17/18 G4: 20/19/18 G5: 21/20/20 G6: 20/18/18 G7: 20/16/16 G8: 20/18/18 African American: G1: 3/3/3 G2: 2/2/2 G3: 7/4/4 G4: 5/5/5 G5: 4/4/4 G6: 3/3/3 G7: 4/4/4 G8: 3/3/3	Sex: Females Age (y) Caucasian: 67 ± 7.3 African American: 65 ± 7.0 Serum 25(OH)D (nmol/L) Caucasian: 49.3 ± 13.3 African American: 45.0 ± 14.8 BMI: NR Ethnicity: Caucasian 84% African American 16% Smoking status: NR Alcohol use: NR Health status: NR Season: Enrolment in winter and spring over 2 years: Apr to May 2007 and Jan to May 2008. [Baseline characteristics published in the earlier publications could not be utilized here, as the results were combined regarding the ethnicities]	Vitamin D₃ Doses (labeled) G1: placebo + calcium G2: vitamin D₃ 400 IU/d [10 μg/d] + calcium G3: vitamin D₃ 800 IU/d [20 μg/d] + calcium G4: vitamin D₃ 1600 IU/d [40 μg/d] + calcium G5: vitamin D₃ 2400 IU/d [60 μg/d] + calcium G6: vitamin D₃ 3200 IU/d [80 μg/d] + calcium G7: vitamin D₃ 4000 IU/d [100 μg/d] + calcium G8: vitamin D₃ 4800 IU/d [120 μg/d] + calcium Calcium to maintain total intake between 1200 to 1400 mg/d (was based on a baseline 7‐day food diary). Average calcium supplement during the study was 600 mg/d at 12 mo. Analysed vitamin D doses G2: 503 IU/d [12.6 μg/d] G3: 910 IU/d [22.8 μg/d] G4: 1532 IU/d [38.3 μg/d] G5: 2592 IU/d [64.8 μg/d] G6: 2947 IU/d [73.7 μg/d] G7: 4209 IU/d [105.2 μg/d] G8: 4937 IU/d [123.4 μg/d] Background vitamin D intake (IU/d) Caucasian: 144 ± 69 IU/d [3.6 ± 1.7 μg/d] African American: 129 ± 85 IU/d [3.2 ± 2.1 μg/d] Background calcium intake (mg/d) Caucasian: 685 ± 289 African American: 524 ± 156 Compliance Pill count method ‐ vitamin D₃ capsules (%): All: 94 on average Pill count method – calcium tablets (%) All: 91 on average Serum 25(OH)D at 1 yr: NR	BMD; DXA ** BMD at baseline: NR ** Assay of serum 25(OH)D: LC–MS	Data extracted: unclear Caucasian and African American combined: BMD, change over 1 yr (%), mean ± SE Femoral neck: G1: −0.32 ± 0.80 G2: 1.89 ± 0.85 G3: 0.23 ± 0.79 G4: 1.06 ± 0.77 G5: −0.26 ± 0.77 G6: 2.20 ± 0.82 G7: 0.72 ± 0.83 G8: 0.53 ± 0.82 P = 0.19 for difference in change between groups. ³⁾ Lumbar spine (L1‐L4): G1: 0.06 ± 0.63 G2: −0.37 ± 0.67 G3: 0.24 ± 0.62 G4: 0.41 ± 0.60 G5: 0.38 ± 0.60 G6: 0.33 ± 0.67 G7: 0.25 ± 0.63 G8: 2.03 ± 0.64 P = 0.25 for difference in change between groups. ³⁾ ³⁾ adjusted for ethnicity.	1

Reference Study Country Duration Funding

Design

Subject characteristics at baseline ^(a)

Intervention ^(a)

Endpoint assessed; method of measurement Endpoint at baseline ^(a) Assay of serum 25(OH)D

Results ^(a)

RoB Tier

Children and adolescents

Al‐Shaar et al. (2013)

Lebanon

Latitude [assumed] 33.9° N

1 yr

Private funding

Based on the same study as El‐Hajj Fuleihan et al. (2006) below but reported different outcomes and groups.

RCT (parallel)

Inclusion criteria:

Aged 10 to 17 y; healthy based on careful physical examination; absence of a history of any disorders or medications known to affect bone metabolism.

Exclusion criteria: Renal disease, liver disease, chronic diarrhea, and gastric and bowel surgery; used high‐dose vitamins within 6 mo of study entry; used corticosteroid therapy, anti‐epileptic drugs, rifampicin, or cholestyramine.

N participants randomised/completed/analysed

Females:

G1: 58/55/55

G2: 62/58/58

G3: 59/55/54

Males:

G1: 61/56/56

G2: 59/56/55

G3: 64/60/60

Sex (% females)

All: 49.3

Age (y)

Females:

G1: 13.60 (11.65–15.65)

G2: 12.56 (11.07–14.75)

G3: 13.08 (11.13–14.72)

Males:

G1: 12.9 (11.8–14.8)

G2: 12.6 (11.2–14.6)

G3: 12.9 (11.4–14.8)

Serum 25(OH)D (ng/mL)

Females:

G1: 11.7 (8.7–11.7) ng/mL [29.3 (21.8–29.3) nmol/L]

G2: 11.3 (8.7–15.6) ng/mL [28.3 (21.8–39.0) nmol/L]

G3: 12.6 (10.0–18.7) ng/mL [31.5 (25.0–46.8) nmol/L]

Males:

G1: 16.0 (12.9–19.5) ng/mL [40.0 (32.3–48.8) nmol/L]

G2: 15.2 (12.1–18.8) ng/mL [38.0 (30.3–47.0) nmol/L]

G3: 15.5 (11.7–18.7) ng/mL [38.8 (29.3–46.8) nmol/L]

BMI (kg/m²)

Females:

G1: 19.9 (17.2–21.8)

G2: 20.2 (17.9–23.0)

G3: 19.4 (17.5–21.9)

Males:

G1: 20.8 (17.0–25.4)

G2: 19.8 (17.3–24.5)

G3: 20.3 (17.6–23.5)

Ethnicity [assumed]:

Arab

Smoking status: NA

Alcohol use: NR

Health status: Healthy.

Season: Recruitment occurred between Dec 2001 and June 2002.

Vitamin D₃

Doses

G1: placebo

G2: vitamin D₃ 1400 IU/wk [35 μg/wk = 5 μg/d]

G3: vitamin D₃ 14 000 IU/wk [350 μg/wk = 50 μg/d]

Analysed doses:

Stated that the vitamin D concentration in the 3 solutions was within 10% of that anticipated based on the label on the bottles and the dilution protocol.

Background vitamin D intake: NR

Background calcium intake (mg/d)

Reported in the earlier publication on girls (El‐Hajj Fuleihan, 2006)

G1: 672 ± 323

G2: 674 ± 364

G3: 686 ± 411

Compliance

Pill count method (%)

Reported in the earlier publication on girls (El‐Hajj Fuleihan, 2006)

Serum 25(OH)D at 1 yr (ng/mL)

G1: 16 ± 8 ng/mL [40 ± 20 nmol/L]

G2: 17 ± 6 ng/mL [42.5 ± 15 nmol/L]

G3: 38 ± 31 ng/mL [95 ± 77.5 nmol/L]

BMD; DXA.

Also measured in hip structural analysis: Cross sectional area, outer diameter, section modulus, and buckling ratio.

****

BMD at baseline (g/cm ² )

Females

Narrow neck:

G1: 0.99 ± 0.2

G2: 0.99 ± 0.2

G3: 0.97 ± 0.2

Shaft:

G1: 1.38 ± 0.24

G2: 1.34 ± 0.24

G3: 1.35 ± 0.24

Intertrochanteric:

G1: 0.94 ± 0.20

G2: 0.91 ± 0.15

G3: 0.89 ± 0.16

Males

Narrow neck:

G1: 1.01 (0.89–1.22)

G2: 1.03 (0.88–1.17)

G3: 0.99 (0.87–1.19)

Shaft:

G1: 1.38 (1.22–1.79)

G2: 1.38 (1.11–1.68)

G3: 1.36 (1.18–1.65)

Intertrochanteric:

G1: 1.05 ± 0.20

G2: 1.03 ± 0.20

G3: 1.03 ± 0.21

****

Assay of serum 25(OH)D: CPBA (Diasorin, Incstar, Saluggia, Italy)

Data extracted: unclear

BMD, change over 1 yr (%), mean ± SE

Females

Narrow neck:

G1: 5.25 ± 0.96

G2: 7.50 ± 0.92

G3: 6.12 ± 0.98

P = 0.72 for difference in change between groups. ⁴⁾

Shaft:

G1: 8.32 ± 0.84

G2: 9.10 ± 0.85

G3: 8.15 ± 0.84

P = 0.70 for difference in change between groups.⁴⁾

Intertrochanteric:

G1: 5.18 ± 0.91

G2: 8.10 ± 0.88

G3: 5.84 ± 0.92

P = 0.06 for difference in change between groups. ⁴⁾

⁴⁾ adjusted for baseline height, percentage change in lean mass and height, sun exposure, physical activity, calcium intake, and menarcheal status.

(Table 4 presents wrong group sizes)

Males

Narrow neck:

G1: 6.86 ± 0.97

G2: 5.88 ± 1.01

G3: 6.02 ± 0.93

P = 0.74 for difference in change between groups. ⁵⁾

Shaft:

G1: 8.04 ± 0.81

G2: 8.05 ± 0.79

G3: 8.37 ± 0.75

P = 0.94 for difference in change between groups. ⁵⁾

Intertrochanteric:

G1: 5.69 ± 0.95

G2: 5.07 ± 0.99

G3: 5.07 ± 0.92

P = 0.87 for difference in change between groups. ⁵⁾

⁵⁾ adjusted for percentage change in lean mass.

Females & Males

No significant differences in %‐changes in cross sectional area, outer diameter, section modulus, or buckling ratio were observed between the groups, apart from the following in girls at the narrow neck:

Outer diameter, change over 1 yr (%), mean ± SE

G1: 2.77 ± 0.50

G2: 0.80 ± 0.48

G3: 1.97 ± 0.51

P = 0.02 for difference in change between groups. ⁴⁾

Buckling ratio, change over 1 yr (%), mean ± SE

G1: −1.98 ± 1.32

G2: −6.53 ± 1.26

G3: −4.16 ± 1.34

P = 0.049 for difference in change between groups. ⁴⁾

1 for females;

2 for males

El‐Hajj Fuleihan et al. (2006)

Lebanon

Latitude [assumed] 33.9° N

1 yr

Private funding

Based on the same study as Al‐Shaar et al. (2013) above but reported different outcomes and groups

RCT (parallel)

Inclusion criteria:

Children and adolescents aged 10 to 17 y; healthy based on careful physical examination and absence of a history of any

disorders or medications known to affect bone metabolism.

It was stated that in boys, there was no consistent positive effect of vitamin D supplementation on BMD or BMC, which was why the paper stated they reported the results mainly on girls.

N participants randomised/completed/analysed:

All (girls)

G1: 58/55/55

G2: 62/58/58

G3: 59/55/55

Premenarcheal

G1: NR/NR/8

G2: NR/NR/12

G3: NR/NR/14

Sex: Females

Premenarcheal (%)

G1: 14.5

G2: 20.7

G3: 25.5

Age (y)

All

G1: 13.6 ± 2.1

G2: 13.0 ± 2.1

G3: 13.1 ± 2.2

Premenarcheal

G1: 10.9 ± 0.6

G2: 10.6 ± 0.6

G3: 10.8 ± 1.1

Serum 25(OH)D (ng/mL)

All

G1: 14 ± 7 ng/mL [35 ± 17.5 nmol/L]

G2: 14 ± 9 ng/mL [35 ± 22.5 nmol/L]

G3: 14 ± 8 ng/mL [35 ± 20 nmol/L]

Premenarcheal

G1: 13 ± 7 ng/mL [32.5 ± 17.5 nmol/L]

G2: 15 ± 6 ng/mL [37.5 ± 15 nmol/L]

G3: 14 ± 5 ng/mL [35 ± 12.5 nmol/L]

BMI: NR

Ethnicity [assumed]:

Arab

Smoking status: NA

Alcohol use: NR

Health status: Healthy.

Season: Recruitment occurred between Dec 2001 and June 2002.

Vitamin D₃

Doses

G1: placebo

G2: vitamin D₃ 1400 IU/wk [35 μg/wk = 5 μg/d]

G3: vitamin D₃ 14 000 IU/wk [350 μg/wk = 50 μg/d]

Analysed doses:

Stated that the vitamin D concentration in the 3 solutions was within 10% of that anticipated based on the label on the bottles and the dilution protocol.

Background vitamin D intake: NR

Background calcium intake (mg/d)

All

G1: 672 ± 323

G2: 674 ± 364

G3: 686 ± 411

Premenarcheal

G1: 805 ± 430

G2: 811 ± 383

G3: 816 ± 570

Compliance

Pill count method (%)

G1: 98 ± 3

G2: 98 ± 3

G3: 97 ± 3

Serum 25(OH)D at 1 yr (ng/mL)

G1: 16 ± 8 ng/mL [40 ± 20 nmol/L]

G2: 17 ± 6 ng/mL [42.5 ± 15 nmol/L]

G3: 38 ± 31 ng/mL [95 ± 77.5 nmol/L]

BMD and BMC; DXA.

****

BMD at baseline: NR

BMC at baseline (g)

All

Total hip:

G1: 24.3 ± 5.4

G2: 22.8 ± 5.5

G3: 22.6 ± 5.9

Lumbar spine:

G1: 41.1 ± 12.0

G2: 37.6 ± 10.7

G3: 39.2 ± 12.9

Femoral neck:

G1: 3.3 ± 0.7

G2: 3.3 ± 0.7

G3: 3.3 ± 0.7

One‐third radius:

G1: 1.4 ± 0.2

G2: 1.3 ± 0.2

G3: 1.3 ± 0.3

Premenarcheal

Total hip:

G1: 17.2 ± 5.3

G2: 15.8 ± 4.2

G3: 17.0 ± 3.8

Lumbar spine:

G1: 25.2 ± 6.4

G2: 25.0 ± 5.2

G3: 27.4 ± 6.3

Femoral neck:

G1: 2.4 ± 0.7

G2: 2.5 ± 0.5

G3: 2.6 ± 0.5

One‐third radius:

G1: 1.0 ± 0.0

G2: 1.0 ± 0.2

G3: 1.0 ± 0.2

****

Assay of serum 25(OH)D: CPBA (Diasorin, Incstar, Saluggia, Italy)

Data extracted: ITT

Stated that the results of ITT analyses were identical with the results of PP analyses in view of the very high compliance and the fact that those who retuned for follow‐up visits and BMD measurements were all taking the study medications.

All

BMD, change over 1 yr (%)

Total hip:

G1: 2.4 ± 4.5

G2: 4.0 ± 4.6

G3: 5.7 ± 5.8

P = 0.003 for difference in change between groups.

Lumbar spine:

G1: 4.0 ± 4.6

G2: 5.0 ± 6.3

G3: 4.3 ± 5.4

P = 0.61 for difference in change between groups.

Femoral neck:

G1: 0.7 ± 4.9

G2: 0.03 ± 4.8

G3: 0.8 ± 5.4

P = 0.67 for difference in % change between groups.

One‐third radius: NR

BMC, change over 1 yr (%)

Total hip:

G1: 7.8 ± 7.7

G2: 11.2 ± 9.3

G3: 12.8 ± 10.5

P = 0.02 for difference in change between groups.

Lumbar spine:

G1: 10.8 ± 8.5

G2: 14.5 ± 12.0

G3: 12.9 ± 10.4

P = 0.20 for difference in change between groups.

Femoral neck:

G1: 3.9 ± 7.2

G2: 4.4 ± 7.8

G3: 5.2 ± 8.0

P = 0.70 for difference in change between groups.

One‐third radius: NR

Premenarcheal

BMD, change over 1 yr (%)

Total hip:

G1: 7.4 ± 7.5

G2: 8.0 ± 4.4

G3: 12.3 ± 6.5

P = 0.11 for difference in change between groups.

Lumbar spine:

G1: 3.4 ± 7.0

G2: 3.2 ± 9.5

G3: 4.4 ± 7.7

P = 0.93 for difference in change between groups.

Femoral neck:

G1: 5.0 ± 3.2

G2: 2.7 ± 5.5

G3: 4.9 ± 5.2

P = 0.45 for difference in % change between groups.

One‐third radius: NR

BMC, change over 1 yr (%)

Total hip:

G1: 12.3 ± 12.4

G2: 18.4 ± 9.1

G3: 23.2 ± 11.0

P = 0.08 for difference in change between groups.

Lumbar spine:

G1: 12.0 ± 9.9

G2: 18.8 ± 13.0

G3: 17.2 ± 10.2

P = 0.40 for difference in change between groups.

Femoral neck:

G1: 7.4 ± 4.5

G2: 9.3 ± 9.3

G3: 11.4 ± 7.9

P = 0.50 for difference in change between groups.

One‐third radius: NR

Postmenarcheal

Stated there were no difference in BMD or BMC among the three treatment groups. Data not shown.

1 for females;

2 for males

Adults

Burt et al. (2019)

Canada

Latitude [assumed] 51.05° N

3 y

Private funding

RCT (parallel)

Inclusion criteria:

Healthy men and women aged 55–70 years; DXA lumbar spine and total hip areal BMD T score

> −2.5 SD, serum 25(OH)D between 30–125 nmol/L, and normal serum calcium (2.10–2.55 mmol/L).

Participants were requested to take no more than 200 IU [5 μg] per day of additional vitamin D (eg. a multivitamin supplement).

Exclusion criteria:

Serum25(OH)D < 30 nmol/L or > 125 nmol/L; serum calcium >2.55 mmol/L or <2.10 mmol/L; vitamin D supplement use >2000 IU/d [50 μg/d] for the past 6 mo; use of bone active medication within the last 2 y; disorders known to affect vitamin D metabolism such as sarcoidosis, renal failure, malabsorption disorders, kidney stone within the past 2 y, or regular use of tanning salons; DXA T score compatible with osteoporosis at the lumbar spine, total hip or femoral neck; and high 10‐year risk (≥20%) for osteoporotic fracture

(as defined by the World Health Organization's Canadian

FRAX calculator).

N participants, randomised/completed/analysed

G1: 109/100/105

G2: 100/94/97

G3: 102/93/101

Sex (% females)

G1: 42.9

G2: 48.5

G3: 47.5

Age (y)

G1: 62.2 ± 4.2

G2: 62.6 ± 4.3

G3: 61.9 ± 4.1

Years since menopause

G1: 12.6 ± 5.9

G2: 11.7 ± 7.3

G3: 12.5 ± 5.6

Serum 25(OH)D (nmol/L)

G1: 76.7 ± 21.0

G2: 81.3 ± 20.1

G3: 78.4 ± 18.4

BMI (kg/m²)

G1: 27.7 ± 4.3

G2: 28.1 ± 5.0

G3: 27.1 ± 4.1

Ethnicity (%)

Non‐Hispanic White:

G1: 93.3

G2: 96.9

G3: 97.0

Non‐Hispanic Black:

G1: 1.0

G2: 1.0

G3: 0

Asian:

G1: 4.7

G2: 2.1

G3: 2.0

Hispanic:

G1: 1.0

G2: 0

G3: 1.0

Smokers (%)

G1: 1.9

G2: 0

G3: 4.0

Alcohol use: NR

Health status: NR

Season: Aug 2013 to Dec 2017.

Vitamin D₃

Doses

G1: vitamin D₃ 400 IU/d [10 μg/d]

G2: vitamin D₃ 4000 IU/d [100 μg/d]

G3: vitamin D₃ 10 000 IU/d [250 μg/d]

Participants not consuming the recommended dietary allowance of calcium (1200 mg/d) received calcium tablets as needed (≤600 mg/d) to approximate a total daily intake of 1200 mg.

Background vitamin D intake: NR

Background calcium intake: NR

Compliance

Pill count method – number of days of supplement administration vs total number of days (%)

All: 99 on average, (range 81–100).

Serum 25(OH)D at 36 mo (nmol/L)

G1: 77.4 ± 17.9

G2: 132.2 ± 28.0

G3: 144.4 ± 40.4

BMD; DXA

vBMD; HR‐pQCT.

Failure load; HR‐pQCT.

Also measured: Cortical porosity, trabecular number.

****

BMD at baseline (g/cm ² )

Total hip:

G1: 1.02 ± 0.14

G2: 1.04 ± 0.14

G3: 1.01 ± 0.14

vBMD at baseline (mg/cm ³ )

Total, Radius:

G1: 324.9 ± 61.5

G2: 335.9 ± 65.3

G3: 329.7 ± 60.0

Total, Tibia:

G1: 301.2 ± 58.3

G2: 314.1 ± 52.9

G3: 306.5 ± 52.6

Trabecular, Radius:

G1: 163.1 ± 40.3

G2: 160.4 ± 39.9)

G3: 155.9 ± 40.2

Trabecular, Tibia:

G1: 176.4 ± 37.7

G2: 174.8 ± 35.2

G3: 171.9 ± 38.7

Cortical, Radius:

G1: 887.6 ± 50.0

G2: 899.2 ± 51.3

G3: 904.0 ± 53.3

Cortical, Tibia:

G1: 853.9 ± 61.5

G2: 868.6 ± 52.9

G3: 871.5 ± 59.0

Failure load at baseline

Radius:

G1: 2700.7 ± 1020.7

G2: 2580.1 ± 990.4

G3: 2556.5 ± 964.4

Tibia:

G1: 7831.3 ± 2420.1

G2: 7660.6 ± 2001.2

G3: 7533.5 ± 2209.9

****

Assay of serum 25(OH)D: CLIA (DiaSorin Liaison XL system)

Data extracted: unclear

BMD at 36 mo (g/cm ² )

Total hip:

G1: 1.02 ± 0.14

G2: 1.03 ± 0.15

G3: 1.00 ± 0.14

BMD, at 36 mo (g/cm ² ), mean, 95% CI

Total hip:

G2 vs G1: 0.0007, −0.0064 to 0.0078

G3 vs G1: 0.0019, −0.0052 to 0.0090

P = 0.87 for group x time interaction.

vBMD at 36 mo (mg/cm ³ )

Total, Radius:

G1: 320.1 ± 61.1

G2: 328.6 ± 66.1

G3: 317.3 ± 61.7

Total, Tibia:

G1: 299.1 ± 58.7

G2: 309.1 ± 54.8

G3: 301.5 ± 54.6

Trabecular, Radius:

G1: 164.8 ± 42.5

G2: 161.5 ± 42.0

G3: 155.1 ± 40.1

Trabecular, Tibia:

G1: 179.1 ± 40.3

G2: 178.3 ± 39.1

G3: 175.2 ± 40.8

Cortical, Radius:

G1: 879.6 ± 51.0

G2: 886.3 ± 52.4

G3: 884.9 ± 54.2

Cortical, Tibia:

G1: 848.1 ± 68.8

G2: 856.6 ± 62.9

G3: 853.7 ± 67.9

vBMD, change over 36 mo (mg/cm ³ ), mean, 95% CI

Total, Radius

G2 vs G1: −3.9, −6.5 to −1.3

G3 vs G1: −7.5, −10.1 to −5.0

P < 0.001 for group x time interaction.

Total, Tibia

G2 vs G1: −1.8, −3.7 to 0.1

G3 vs G1: −4.1, −6.0 to −2.2

P < 0.001 for group x time interaction.

Trabecular, Radius

G2 vs G1: −0.95, −2.6 to 0.7

G3 vs G1: −2.71, −4.3 to −1.1

P = 0.012 for group x time interaction.

Trabecular, Tibia

G2 vs G1: 0.20, −0.1 to 1.5

G3 vs G1: −1.1, −2.4 to 0.2

P = 0.127 for group x time interaction.

Cortical, Radius

G2 vs G1: −6.3, −11.1 to −1.5

G3 vs G1: −8.6, −13.3 to −3.8

P = 0.001 for group x time interaction.

Cortical, Tibia

G2 vs G1: −4.2, −9.8 to 1.2

G3 vs G1: −9.8, −14.8 to −4.0

P = 0.004 for group x time interaction.

Failure load at 36 mo

Radius:

G1: 2694.8 ± 1022.7

G2: 2550.5 ± 994.3

G3: 2470.6 ± 1001.5

P = 0.12 for group x time interaction.

Tibia:

G1: 7785.2 ± 2443.7

G2: 7576.9 ± 2125.0

G3: 7413.0 ± 2265.1

P = 0.06 for group x time interaction.

Grimnes et al. (2012)

Norway

Latitude 69° N

1 yr

Private funding

RCT (parallel)

Inclusion criteria:

Postmenopausal women aged 50–80 years old with a T‐score in total hip or lumbar spine (L2–4) ≤ −2.0.

Exclusion criteria:

Use of hormone replacement therapy or other therapy affecting bone remodeling during the last 12 months before enrolment; use of steroids, renal stone disease, systolic blood pressure > 175 mmHg or diastolic blood pressure > 105 mmHg, serum creatinine >110 μmol/l, suspected primary hyperparathyroidism (serum calcium >2.55 mmol/l, serum calcium >2.50 mmol/l combined with plasma PTH >5.0 pmol/l, or serum calcium >2.45 mmol/l combined with plasma PTH >7.0 pmol/l), or chronic disease like ischemic heart disease, diabetes, granulomatous disease, and cancer.

N participants randomised/completed/analysed:

G1: 148/140/ITT 148, PP 140

G2: 149/135/ITT 149, PP 135

Sex: Females

Age (y)

G1: 63.5 ± 6.8

G2: 62.9 ± 7.6

Serum 25(OH)D (nmol/L)

G1: 71.2 ± 22.3

G2: 70.7 ± 23.0

BMI (kg/m²)

G1: 24.6 ± 3.2

G2: 25.0 ± 3.4

Ethnicity [assumed]: Majority Caucasian

Smoking status (%)

Current smokers:

G1: 38

G2: 37

Former smokers:

G1: 39

G2: 40

Alcohol use: NR

Health status (%)

Asthma/COPD:

G1: 10

G2: 6

Thyroid disease:

G1: 9

G2: 13

Arthrosis:

G1: 9

G2: 11

Other musculoskeletal disease:

G1: 11

G2: 15

Hypertension:

G1: 19

G2: 17

Hypercholesterolemia:

G1: 11

G2: 12

Vitamin D₃

Doses

G1: vitamin D₃ 800 IU/d [20 μg/d] + calcium 1000 mg/d

G2: vitamin D₃ 40 000 IU/wk [5714 IU/d = 142.9 μg/d] + 800 IU/day [20 μg/d] = 6514.29 IU/d [162.9 μg/d] + calcium 1000 mg/d

Background vitamin D intake (μg/d)

G1: 8.1 ± 6.0

G2: 9.1 ± 6.2

Background calcium intake (mg/d)

G1: 1044 ± 552

G2: 1062 ± 524

Compliance

Pill count method (%)

All (vitamin D): 97

All (calcium): 92.

Stated no differences across groups.

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

G1: 18.0 ± 18.9

G2: 114.7 ± 34.6

PP population.

BMD; DXA.

****

BMD at baseline (g/cm ² )

Total hip:

G1: 0.791 ± 0.082

G2: 0.790 ± 0.073

Lumbar spine (L2‐L4):

G1: 0.902 ± 0.079

G2: 0.901 ± 0.072

Femoral neck

G1: 0.757 ± 0.079

G2: 0.758 ± 0.066

****

Assay of serum 25(OH)D: LC–MS/MS (In‐house, Hormone Laboratory, Haukeland

University Hospital)

Data extracted: ITT

BMD, change over 12 mo (%)

Total hip:

G1: 0.56 ± 1.70

G2: 0.31 ± 1.59

P = 0.20 for difference in change between groups.

Lumbar spine (L2‐L4):

G1: 0.32 ± 3.23

G2: 0.25 ± 3.19.

P = 0.86 for difference in change between groups.

Femoral neck:

G1: 0.17 ± 1.87

G2: 0.03 ± 2.08

P = 0.53 for difference in change between groups.

Jorde et al. (2010)

Norway

Latitude 70° N

1 yr

Mixed funding

RCT (parallel)

Inclusion criteria:

Males and females 21–70 y, with BMI 28.0–47.0 kg/m².

Exclusion criteria:

Diabetes or a history of coronary infarction, angina pectoris, stroke, renal stone disease, or sarcoidosis; serum calcium >2.55 mmol/L, males with serum creatinine >129 μmol/L and females with serum creatinine >104 μmol/L; use of bisphosphonates or oestrogen (for contraception or replacement); a weight loss of >10% of total body weight during the last 6 mo; use of anti‐depressant drugs or weight reducing drugs; participating in an organized weight loss program; pregnancy or lactating women; women planning to become pregnant in the next 12 mo or < 50 years without adequate contraception (contraceptive pills, implantable subdermal contraceptive rods, contraceptive dermal patches, injectable contraceptives, vaginal contraceptive rings, or intrauterine devices, with pearl index <1.0).

N participants randomised/completed/analysed:

G1: 142/105/105

G2: 132/97/97

G3: 147/110/110

Sex (% females)

G1: 61.0

G2: 59.8

G3: 60.0

Postmenopausal (%)

G1: 55%

G2: 48%

G3: 44%

Age (y)

G1: 50.8 ± 10.7

G2: 47.7 ± 11.6

G3: 47.3 ± 11.1

Serum 25(OH)D (nmol/L)

G1: 60.1 ± 22.3

G2: 58.3 ± 21.2

G3: 61.3 ± 20.7

BMI (kg/m²)

G1: 35.2 ± 3.9

G2: 33.7 ± 3.5

G3: 34.4 ± 3.9

Ethnicity [assumed]: Majority Caucasian

Smokers (%)

G1: 17.1

G2: 20.6

G3: 20.9

Alcohol use: NR

Health status: Healthy overweight.

Season: Recruitment occurred in Nov 2005 to October 2006.

Vitamin D₃

Doses

G1: placebo + calcium 500 mg/d

G2: vitamin D₃ 20 000 IU/wk [2857 IU/d = 71.4 μg/d] + calcium 500 mg/d

G3: vitamin D₃ 40 000 IU [5714 IU/d = 142.9 μg/d] + calcium 500 mg/d

Background vitamin D intake: NR

Background calcium intake: NR

Compliance

Pill count method – vitamin D/placebo capsules (%)

G1: 96

G2: 96

G3: 95

Pill count method – calcium tablets (%)

G1: 83

G2: 84

G3: 82

Serum 25(OH)D at 1 yr (nmol/L)

G1: 57.9 ± 20.4

G2: 99.7 ± 20.3

G3: 140.9 ± 34.7

BMD; DXA.

****

BMD at baseline (g/cm²)

Total hip:

G1: 1.092 ± 0.130

G2: 1.067 ± 0.128

G3: 1.107 ± 0.133

Lumbar spine (L2‐L4):

G1: 1.251 ± 0.170

G2: 1.235 ± 0.161

G3: 1.270 ± 0.155

****

Assay of serum 25(OH)D: RIA (DiaSorin)

Data extracted: PP

BMD, change over 1 yr (g/cm ² )

Total hip

G1: 0.009 ± 0.017

G2: 0.011 ± 0.014

G3: 0.008 ± 0.014

Lumbar spine (L2‐L4):

G1: 0.007 ± 0.042

G2: 0.008 ± 0.039

G3: 0.008 ± 0.036

P=NS for all comparisons vs G1 (exact values NR).

Rahme et al. (2017)

Lebanon

Latitude [assumed] 33.9° N

1 yr

Mixed funding

RCT (parallel)

Inclusion criteria:

Ambulatory elderly, aged ≥65 y; overweight (BMI >25 kg/m²), serum 25(OH)D between 10 and 30 ng/mL [25 and 75 nmol/L] at screening.

Exclusion criteria:

Prediabetes if on oral

hypoglycemic drugs; diabetes (fasting plasma glucose

≥126 mg/dL or glycated haemoglobin ≥6.5%); severe chronic diseases, or major organ failure (severe heart failure [stage III or IV], liver failure and cirrhosis, kidney failure [estimated glomerular filtration rate < 30 mL/min], cancer, and autoimmune diseases); conditions or being on medications known to affect bone metabolism; osteomalacia, a history of kidney stones, fragility fractures, or a 10‐yr fracture risk for major osteoporotic fractures exceeding 10% based on Fracture Risk Assessment Tool Lebanon risk calculator at study entry.

N participants randomised/completed/analysed:

G1: 128/112/112

G2: 129/110/110

Sex (% females)

G1: 53.6

G2: 57.3

Age (y)

G1: 71.0 ± 4.7

G2: 71.2 ± 4.8

Serum 25(OH)D (ng/mL)

G1: 20.0 ± 7 ng/mL [50.0 ± 17.5 nmol/L]

G2: 20.9 ± 8.2 ng/mL [52.3 ± 20.5 nmol/L]

BMI (kg/m²)

G1: 29.7 ± 4.6

G2: 30.6 ± 4.4

Ethnicity [assumed]:

Arab

Smoking status: NR

Alcohol use: NR

Health status: Overweight

Season: Screening occurred between Jan 2011 and July 2013; the study ended in July 2014.

Vitamin D₃

Doses (labeled)

G1: placebo + vitamin D₃ 500 IU/d [12.5 μg/d] + calcium 1000 mg/d

G2: vitamin D₃ 20 000 IU/wk [500 μg/wk] + vitamin D₃ 500 IU/d [12.5 μg/d] + calcium 1000 mg/d = vitamin D₃ 3357 IU/d [83.9 μg/d] + calcium 1000 mg/d

Analysed vitamin D₃ doses:

G1: 600 IU/d [15 μg/d]

G2: 22 000 IU/wk + 600 IU/d [15 μg/d] = 3742.86 IU/d [93.6 μg/d]

Background vitamin D intake: NR

Background calcium intake (mg/d)

G1: 453 ± 323

G2: 397 ± 257

Background calcium + vitamin D supplement use (%)

G1: 11 ± 10

G2: 11 ± 10

Compliance

Pill count method (%)

All: >90 for both calcium and vitamin D pills, for both groups.

Serum 25(OH)D at 12 mo (ng/mL)

G1: 25.9 ± 6.9 ng/mL [64.8 ± 17.3 nmol/L]

G2: 36.0 ± 9.7 ng/mL [90.0 ± 24.3 nmol/L]

BMD; DXA.

****

BMD at baseline (g/cm ² )

Total hip:

G1: 0.826 ± 0.119

G2: 0.824 ± 0.118

Lumbar spine:

G1: 0.886 ± 0.154

G2: 0.890 ± 0.150

Femoral neck:

G1: 0.676 ± 0.102

G2: 0.671 ± 0.101

****

Assay of serum 25(OH)D: LC–MS (Mayo Clinic, Rochester, MN, USA)

Data extracted: PP

BMD at 12 mo (g/cm ² )

Total hip:

G1: 0.831 ± 0.121

G2: 0.828 ± 0.118

Lumbar spine:

G1: 0.901 ± 0.162

G2: 0.900 ± 0.145

Femoral neck:

G1: 0.682 ± 0.100

G2: 0.675 ± 0.099

BMD, change over 12 mo (%)

Total hip:

G1: 0.50 ± 2.26

G2: 0.47 ± 2.22

P = 0.909 for difference in % change between groups.

Lumbar spine:

G1: 1.34 ± 3.42

G2: 1.65 ± 3.21

P = 0.512 for difference in % change between groups.

Femoral neck:

G1: 0.55 ± 3.78

G2: 0.66 ± 4.16

P = 0.833 for difference in % change between groups.

Smith et al. (2018)

ViDOS

USA

Latitude 41° N

1 yr

Mixed funding

RCT (parallel)

Inclusion criteria:

Caucasian and African

American postmenopausal women aged 57 to 90 years; vitamin D insufficiency defined as serum 25(OH)D ≤ 50 nmol/L.

Exclusion criteria:

Any significant disease or medications affecting calcium and bone metabolism: significant health problems, cancer within the last 10 y (except skin), previous hip fracture, hemiplegia, uncontrolled type 1 and type 2 diabetes, active kidney stones or history of kidney stones more than twice

in their lifetime, body mass index (BMI) greater than 45 kg/m², serum 25(OH)D below 12.5 nmol/L, and chronic medical conditions involving liver, kidney, alcoholism or rheumatoid arthritis. Use of fluoride, bisphosphonates for more than 3 mo, PTH or derivatives within the last 6 months, calcitonin, estrogen, corticosteroid therapy of more

than 10 mg/d, drugs interfering with vitamin D metabolism, such as phenytoin or phenobarbital, and high‐dose thiazide therapy (>37.5 mg/d).

N participants,

randomised/completed/analysed

Caucasian:

G1: 21/18/19

G2: 20/16/18

G3: 21/17/18

G4: 20/19/18

G5: 21/20/20

G6: 20/18/18

G7: 20/16/16

G8: 20/18/18

African American:

G1: 3/3/3

G2: 2/2/2

G3: 7/4/4

G4: 5/5/5

G5: 4/4/4

G6: 3/3/3

G7: 4/4/4

G8: 3/3/3

Sex: Females

Age (y)

Caucasian: 67 ± 7.3

African American: 65 ± 7.0

Serum 25(OH)D (nmol/L)

Caucasian: 49.3 ± 13.3

African American: 45.0 ± 14.8

BMI: NR

Ethnicity:

Caucasian 84%

African American 16%

Smoking status: NR

Alcohol use: NR

Health status: NR

Season: Enrolment in winter and spring over 2 years: Apr to May 2007 and Jan to May 2008.

[Baseline characteristics published in the earlier publications could not be utilized here, as the results were combined regarding the ethnicities]

Vitamin D₃

Doses (labeled)

G1: placebo + calcium

G2: vitamin D₃ 400 IU/d [10 μg/d] + calcium

G3: vitamin D₃ 800 IU/d [20 μg/d] + calcium

G4: vitamin D₃ 1600 IU/d [40 μg/d] + calcium

G5: vitamin D₃ 2400 IU/d [60 μg/d] + calcium

G6: vitamin D₃ 3200 IU/d [80 μg/d] + calcium

G7: vitamin D₃ 4000 IU/d [100 μg/d] + calcium

G8: vitamin D₃ 4800 IU/d [120 μg/d] + calcium

Calcium to maintain total intake between 1200 to 1400 mg/d (was based on a baseline 7‐day food diary). Average calcium

supplement during the study was 600 mg/d at

12 mo.

Analysed vitamin D doses

G2: 503 IU/d [12.6 μg/d]

G3: 910 IU/d [22.8 μg/d]

G4: 1532 IU/d [38.3 μg/d]

G5: 2592 IU/d [64.8 μg/d]

G6: 2947 IU/d [73.7 μg/d]

G7: 4209 IU/d [105.2 μg/d]

G8: 4937 IU/d [123.4 μg/d]

Background vitamin D intake (IU/d)

Caucasian: 144 ± 69 IU/d [3.6 ± 1.7 μg/d]

African American: 129 ± 85 IU/d [3.2 ± 2.1 μg/d]

Background calcium intake (mg/d)

Caucasian: 685 ± 289

African American: 524 ± 156

Compliance

Pill count method ‐ vitamin D₃ capsules (%):

All: 94 on average

Pill count method – calcium tablets (%)

All: 91 on average

Serum 25(OH)D at 1 yr: NR

BMD; DXA

****

BMD at baseline: NR

****

Assay of serum 25(OH)D: LC–MS

Data extracted: unclear

Caucasian and African American combined:

BMD, change over 1 yr (%), mean ± SE

Femoral neck:

G1: −0.32 ± 0.80

G2: 1.89 ± 0.85

G3: 0.23 ± 0.79

G4: 1.06 ± 0.77

G5: −0.26 ± 0.77

G6: 2.20 ± 0.82

G7: 0.72 ± 0.83

G8: 0.53 ± 0.82

P = 0.19 for difference in change between groups. ³⁾

Lumbar spine (L1‐L4):

G1: 0.06 ± 0.63

G2: −0.37 ± 0.67

G3: 0.24 ± 0.62

G4: 0.41 ± 0.60

G5: 0.38 ± 0.60

G6: 0.33 ± 0.67

G7: 0.25 ± 0.63

G8: 2.03 ± 0.64

P = 0.25 for difference in change between groups. ³⁾

³⁾ adjusted for ethnicity.

Abbreviations: BMC: bone mineral content; BMD: bone mineral density; BMI: body mass index; CI: confidence interval; CLIA: chemiluminescence immunoassay; DXA: dual‐energy x‐ray absorptiometry; CPBA: competitive protein binding assay; G: group; HR‐pQCT: high‐resolution peripheral quantitative computed tomography; ITT: intention‐to‐treat; LC–MS: liquid chromatography mass spectrophotometry; LC–MS/MS: liquid chromatography tandem mass spectrophotometry; NA: not applicable; NR: not reported; NS: non‐significant; PP: per‐protocol; RIA: radioimmunoassay; RCT: randomised controlled trial; SD: standard deviation; SE: standard error; vBMD: volumetric bone mineral density; 25(OH)D: 25‐hydroxyvitamin D; y, years.

^(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.