. 2022 Oct 26;34(11):2603–2623. doi: 10.1007/s40520-022-02279-6

Table 1.

Meta-analyses on vitamin D supplementation and fractures

Author, year, studies	Intervention tested	Target population and limitations	Results for fractures
Bischoff-Ferrari et al. (2009) [51] 12 RCTs (non- vertebral fractures) N = 42,279 8 RCTs (hip fractures) N = 40,886	Vit D ± calcium Vit D ≤ 400 IU/d in 3 trials whereas the other 9 RCTs had mean intakes of 482–770 IU/d	Mean age of 78 years, 89% women Duration from 12 to 84 months	Pooled relative risk 0.86 (95% CI 0.77–0.96) for prevention of non-vertebral fracture and 0.91 (95% CI 0.78–1.05) for hip fracture
	Calcium 500–1200 mg/d in combination with vit D in 7 RCTs		For the higher dose (> 400 IU), pooled RR 0.80 (95% CI 0.72–0.89); n = 33,265, 9 trials for non-vertebral fractures and 0.82 (95% CI 0.69–0.97); n = 31,872, 5 trials for hip fractures
Lai et al. (2010) [52] 7 RCTs N = 12,762	Vit D alone 400–1100 IU/day in 6 RCTs Vit D 800 IU + calcium 1000 mg/day in 1 RCT	RCT including a minimum of 100 participants with at least one radiologically confirmed hip fracture in each group	RR 1.13 (95% CI 0.98–1.29) for hip fractures No significant variations found between results of studies randomizing participants to: < 800 IU/day 1.14 (95% CI 0.86–1.49) or ≥ 800 IU/day 1.12 (95% CI 0.96–1.32)
Bergman et al. (2010) [53] 8 RCTs N = 12,658	Vit D ± calcium	4 RCTs on non-vertebral fracture, n = 3510 5 RCTs on hip fracture, n = 7473	Vit D3 + calcium compared to placebo: OR 0.77 (95% CI 0.6–0.93) for non-vertebral fracture and OR 0.70 (95% CI 0.53–0.90) for hip fracture
Chung et al. (2011) [54] 16 RCTs N = 19,878	Vit D (400–1370 IU/d) alone 5 RCTs—N = 14,583	Elderly men and women with follow-up ranging from 7 months to 5 years	Pooled relative risk 1.03 [95% CI 0.84 to 1.26], with high heterogeneity
	Vit D (300–1000 IU/d) + calcium 500–1200 mg/d 11 RCTs—N = 52,915		Pooled relative risk, 0.88 [95% CI 0.78–0.99], with moderate heterogeneity Significant risk reduction among institutionalized elderly persons (relative risk, 0.71 [95% CI 0.57–0.89])
Murad et al. (2012) [55] Network meta-analysis	Vit D ± calcium	Median age, 64 years; 86% females and 88% Caucasians; median follow-up, 24 months	OR 0.81 (95% CI 0.68–0.96) for hip fracture and OR 0.94 (95% CI 0.84–1.02) for non-vertebral fracture Vit D and calcium given separately were ineffective
Avenell et al. (2014) [47] 31 RCTs N = 36,282	Vit D alone 11 RCTs, N = 27 693 15 RCTs, N = 28 272	12/31 RCTs had participants with a mean or median age of 80 years or over	RR 1.12 (95% CI 0.98–1.29) for hip fracture RR 1.03 (95% CI 0.96–1.11) for any fracture
	Vit D + calcium 9 RCTs, N = 49 853 10 RCTs, N = 49 976 Institutional (2 RCTs), N = 3853	Prevention of fractures in community, nursing home or hospital inpatient populations	RR 0.84 (95% CI 0.74–0.96) for hip fracture RR 0.95 (95% CI 0.90–0.99) for any fracture **RR 0.75 (95% CI 0.62, 0.92) and RR 0.85 (95% CI 0.74, 0.98) for hip and any fracture, respectively in institutionalized-dwelling subjects**
Weaver et al. (2016) [56] 8 RCTs N = 30,970	Vit D + calcium	Mostly adults aged 65 + years – Excluded studies that tested vit D without calcium – Included 40% of the literature that contributed to current guidelines on vit D	15% reduction of total fractures (RR = 0.85; 95% CI 0.73–0.98) 30% reduction of hip fractures (RR = 0.70; 95% CI 0.56–0.87)
Zhao et al. (2017) [57] 33 RCTs (n = 51,145)	Vit D, Calcium and Vit D + calcium	Community-dwelling participants aged 50 + years for primary prevention without a prior fracture; baseline 25(OH)D ≈ 50 nmol/L Exclusion of older adults living in institutions, most vulnerable to low calcium intake, vitamin D deficiency and fracture risk 11 out of 33 with follow-up of ≤ 12 months with little potential to show benefit on fracture reduction, 4 trials had an open study design without a treatment in the control group No adjustment for adherence For vit D alone 8 of the 12 trials gave vit D in bolus doses (orally or intramuscular administration), which has repeatedly raised concerns in the literature about promoting both falls and fractures	No significant effect of calcium, vit D or both on risk of hip fracture compared with placebo or no treatment: Calcium: RR = 1.53 (95% CI 0.97–2.42) Vit D: RR = 1.21 (95% CI 0.99–1.47) Vit D + calcium RR = 1.09 (95% CI 0.85–1.39) No significant benefit on any intervention on the incidence of non-vertebral, vertebral, or total fractures
Kahwati et al. (2018) [58] 11 RCTs (N = 51,419)	Vit D, Calcium and Vit D + calcium	Community-dwelling adults aged 50 + years not at risk for osteoporosis or vit D deficiency Panel acknowledged limited trial data for primary prevention	For vit D doses greater than 400 IU (according to current recommendations), the panel concluded that there is insufficient evidence to assess a benefit from vit D
Bolland et al. (2018) [59] 81 unblinded and blinded randomized trials among (n = 44,790)	Vit D compared to untreated controls, placebo or another dose of vit D	Adults aged 50 + years Authors excluded trials that combined vit D with calcium and thereby 40% of the literature that contributed to current guidelines Authors included large bolus doses that have consistently increased the risk of falls and fractures Biased reporting on low-dose vit D with 800 IU vit D trials	No benefit on fractures Re-analysis of 800–1000 IU vit D trials of this meta-analysis and excluding bolus trials suggests a significant 14% reduction in total fractures
Hu et al. (2019) [60] 25 RCTs N = 43,510	Vit D, Calcium and Vit D + calcium	Adults aged older than 50 years and living in their communities and only studies that lasted more than a year	No reduction of the risk of total, hip and vertebral fractures using different concentrations of vit D, calcium or their combination compared with placebo or no treatment
Yao et al. (2019) [61] 11 RCTs N = 34,243 6 RCTs N = 49,282	Vit D alone (daily or intermittent dose of 400–30 000 IU) 11 RCTs	Mean age 65.9–85.0 years, baseline 25(OH)D 26.5–65.8 nmol/L, mean duration 3 yrs. Yielding a median difference in 25[OH]D concentration of 21 nmol/L	Vit D alone: no reduction of risk of any fracture (RR 1.06; 95% CI 0.98–1.14) or hip fracture (RR 1.14; 95% CI 0.98–1.32)
	Vit D (400–800 IU daily) + calcium (1000–1200 mg daily) 6 RCTs	Constrained by infrequent intermittent dosing, low daily doses of vit D, or an inadequate number of participants Yielding a median difference in 25(OH)D concentration of 23 nmol/L	↓ 6% of any fracture (RR 0.94; 95% CI 0.89–0.99) and ↓ 16% of hip fracture (RR 0.84; 95% CI 0.72–0.97)
Eleni et al. (2020) [62] 10 RCTs N = 74,325	Vit D + calcium	Patients aged 50 years or older Reported on fractures as a primary outcome	RR 0.74 (95% CI 0.58–0.94) for total fracture RR: 0.61 (95% CI 0.4–0.92) for hip fracture 8 RCTs, N = 68,957
Thanapluetiwong et al. (2020) [63] 26 RCTs N = 40,209	Vit D ± calcium	Major populations were elderly women with age less than 80 years	Vit D alone failed to show any fracture lowering benefit, RR 0.949 (95% CI 0.846–1.064) Vit D + calcium significantly lower fracture rates, RR 0.859 (95% CI 0.741–0.996)
Li et al. (2021) [64] 33 RCTs N = 83,083	Vit D ± calcium	No younger than 47 years old; Follow-up ranged from 3 to 84 months Fracture cases confirmed with hospital diagnosis, medical records, or World Health Organization diagnostic criteria; subjects not treated with any osteoporosis medications and did not have any special physical training;	Vit D alone: no reduction of the risk of total fractures (RR 0.96 (95% CI 0.87–1.05) Vit D3 (700–800 IU/d) + calcium: significant reduction of total (RR 0.85 (95% CI 0.77–0.95), hip (RR 0.81 (95% CI 0.68–0.97), and non-vertebral fractures (RR 0.84 (95% CI 0.74–0.95), in a pairwise meta-analysis
Chakhtoura et al. (2022) [65] Umbrella review of meta-Analyses 25 RCTs	Vit D + calcium—13 SR/MAs	Mean age between 62 and 85 years	Vit D + calcium: ↓ risk of hip fractures in 8/12 SRs/MAs (RR 0.61–0.84)
	Vit D alone—19 SR/MAs Vit D dose 400–800 IU/day	Trials extended from 1 to 7 years 5 SRs/MAs reported on baseline 25(OH)D (20.9–83.8 nmol/L)	↓ risk of any fractures in 7/11 SRs/MAs (RR 0.74–0.95)
	6 SR/MAs included 1 trial providing a high dose of 300,000 IU once Calcium dose was 500–1200 mg/day		No fracture risk reduction in SRs/MAs exclusively evaluating community-dwelling individuals or in those on vit D alone compared to placebo/control
Kong et al. (2022) [66] 32 RCTs N = 104,363 16 RCTs N = 36.793 for fracture outcome	Vit D (median dose of 800 IU/d) ± calcium 8 studies reported < 800 IU/day	Most studies included women with 75% of participants (range 15–100%)	Vit D 800–1000 IU/d: Pooled relative risk 0.87 (95% CI 0.78–0.97) for osteoporotic fractures
	15 studies 800–1000 IU/day, and	Median age was 72 years (range 53–85)	No reduction of hip fractures RR 0.84 (95% CI 0.64–1.10
	9 studies > 1000 IU/day 26 studies reported daily administration, while 6 reported intermittent administration	Median follow-up duration was 24 months (range 9–120)	Vit D 800 to 1000 IU/d + calcium: pooled RR 0.88 (95% CI 0.78–1.00) for osteoporotic fractures

Author, year, studies

Intervention tested

Target population and limitations

Results for fractures

Bischoff-Ferrari et al. (2009) [51]

12 RCTs (non- vertebral fractures)

N = 42,279

8 RCTs (hip fractures)

N = 40,886

Vit D ± calcium

Vit D ≤ 400 IU/d in 3 trials whereas the other 9 RCTs had mean intakes of 482–770 IU/d

Mean age of 78 years, 89% women

Duration from 12 to 84 months

Pooled relative risk 0.86 (95% CI 0.77–0.96) for prevention of non-vertebral fracture and 0.91 (95% CI 0.78–1.05) for hip fracture

Calcium 500–1200 mg/d in combination with vit D in 7 RCTs

For the higher dose (> 400 IU), pooled RR 0.80 (95% CI 0.72–0.89); n = 33,265, 9 trials for non-vertebral fractures and 0.82 (95% CI 0.69–0.97); n = 31,872, 5 trials for hip fractures

Lai et al. (2010) [52]

7 RCTs

N = 12,762

Vit D alone 400–1100 IU/day in 6 RCTs

Vit D 800 IU + calcium 1000 mg/day in 1 RCT

RCT including a minimum of 100 participants with at least one radiologically confirmed hip fracture in each group

RR 1.13 (95% CI 0.98–1.29) for hip fractures

No significant variations found between results of studies randomizing participants to:

< 800 IU/day 1.14 (95% CI 0.86–1.49) or

≥ 800 IU/day 1.12 (95% CI 0.96–1.32)

Bergman et al. (2010) [53]

8 RCTs

N = 12,658

Vit D ± calcium

4 RCTs on non-vertebral fracture, n = 3510

5 RCTs on hip fracture, n = 7473

Vit D3 + calcium compared to placebo:

OR 0.77 (95% CI 0.6–0.93) for non-vertebral fracture and OR 0.70 (95% CI 0.53–0.90) for hip fracture

Chung et al. (2011) [54]

16 RCTs

N = 19,878

Vit D (400–1370 IU/d) alone

5 RCTs—N = 14,583

Elderly men and women with follow-up ranging from 7 months to 5 years

Pooled relative risk 1.03 [95% CI 0.84 to 1.26], with high heterogeneity

Vit D (300–1000 IU/d) + calcium 500–1200 mg/d

11 RCTs—N = 52,915

Pooled relative risk, 0.88 [95% CI 0.78–0.99], with moderate heterogeneity

Significant risk reduction among institutionalized elderly persons (relative risk, 0.71 [95% CI 0.57–0.89])

Murad et al. (2012) [55]

Network meta-analysis

Vit D ± calcium

Median age, 64 years; 86% females and 88% Caucasians; median follow-up, 24 months

OR 0.81 (95% CI 0.68–0.96) for hip fracture and OR 0.94 (95% CI 0.84–1.02) for non-vertebral fracture

Vit D and calcium given separately were ineffective

Avenell et al. (2014) [47]

31 RCTs

N = 36,282

Vit D alone

11 RCTs, N = 27 693

15 RCTs, N = 28 272

12/31 RCTs had participants with a mean or median age of 80 years or over

RR 1.12 (95% CI 0.98–1.29) for hip fracture

RR 1.03 (95% CI 0.96–1.11) for any fracture

Vit D + calcium

9 RCTs, N = 49 853

10 RCTs, N = 49 976

Institutional (2 RCTs), N = 3853

Prevention of fractures in community, nursing

home or hospital inpatient populations

RR 0.84 (95% CI 0.74–0.96) for hip fracture

RR 0.95 (95% CI 0.90–0.99) for any fracture

RR 0.75 (95% CI 0.62, 0.92) and RR 0.85 (95% CI 0.74, 0.98) for hip and any fracture, respectively in institutionalized-dwelling subjects

Weaver et al. (2016) [56]

8 RCTs

N = 30,970

Vit D + calcium

Mostly adults aged 65 + years

– Excluded studies that tested vit D without calcium

– Included 40% of the literature that contributed to current guidelines on vit D

15% reduction of total fractures (RR = 0.85; 95%

CI 0.73–0.98)

30% reduction of hip fractures (RR = 0.70; 95%

CI 0.56–0.87)

Zhao et al. (2017) [57]

33 RCTs (n = 51,145)

Vit D, Calcium and Vit D + calcium

Community-dwelling participants aged 50 + years for primary prevention without a prior fracture; baseline 25(OH)D ≈ 50 nmol/L

Exclusion of older adults living in institutions, most vulnerable to low calcium intake, vitamin D deficiency and fracture risk

11 out of 33 with follow-up of ≤ 12 months with little potential to show benefit on fracture reduction, 4 trials had an open study design without a treatment in the control group

No adjustment for adherence

For vit D alone 8 of the 12 trials gave vit D in bolus doses (orally or intramuscular administration), which has repeatedly raised concerns in the literature about promoting both falls and fractures

No significant effect of calcium, vit D or both on risk of hip fracture compared with placebo or no treatment:

Calcium: RR = 1.53 (95% CI 0.97–2.42)

Vit D: RR = 1.21 (95% CI 0.99–1.47)

Vit D + calcium RR = 1.09 (95% CI 0.85–1.39)

No significant benefit on any intervention on the

incidence of non-vertebral, vertebral, or total fractures

Kahwati et al. (2018) [58]

11 RCTs (N = 51,419)

Vit D, Calcium and Vit D + calcium

Community-dwelling adults aged 50 + years not at risk for osteoporosis or vit D deficiency

Panel acknowledged limited trial data for primary prevention

For vit D doses greater than 400 IU (according

to current recommendations), the panel concluded that there is insufficient evidence to assess a benefit from vit D

Bolland et al. (2018) [59]

81 unblinded and blinded randomized trials among (n = 44,790)

Vit D compared to untreated controls, placebo or another dose of vit D

Adults aged 50 + years

Authors excluded trials that combined vit D with calcium and thereby 40% of the literature that contributed to current guidelines

Authors included large bolus doses that have consistently increased the risk of falls and fractures

Biased reporting on low-dose vit D with 800 IU vit D trials

No benefit on fractures

Re-analysis of 800–1000 IU vit D trials of this meta-analysis and excluding bolus trials suggests a significant 14% reduction in total fractures

Hu et al. (2019) [60]

25 RCTs

N = 43,510

Vit D, Calcium and Vit D + calcium

Adults aged older than 50 years and living in their communities and only studies that lasted more than a year

No reduction of the risk of total, hip and vertebral fractures using different concentrations of vit D, calcium or their combination compared with placebo or no treatment

Yao et al. (2019) [61]

11 RCTs N = 34,243

6 RCTs N = 49,282

Vit D alone (daily or intermittent dose of 400–30 000 IU)

11 RCTs

Mean age 65.9–85.0 years, baseline 25(OH)D 26.5–65.8 nmol/L, mean duration 3 yrs. Yielding a median difference in 25[OH]D concentration of 21 nmol/L

Vit D alone: no reduction of risk of

any fracture (RR 1.06; 95% CI 0.98–1.14) or

hip fracture (RR 1.14; 95% CI 0.98–1.32)

Vit D (400–800 IU daily) + calcium (1000–1200 mg daily)

6 RCTs

Constrained by infrequent intermittent dosing, low daily doses of vit D, or an inadequate number of participants

Yielding a median difference in 25(OH)D concentration of 23 nmol/L

↓ 6% of any fracture (RR 0.94; 95% CI 0.89–0.99) and

↓ 16% of hip fracture (RR 0.84; 95% CI 0.72–0.97)

Eleni et al. (2020) [62]

10 RCTs

N = 74,325

Vit D + calcium

Patients aged 50 years or older

Reported on fractures as a primary outcome

RR 0.74 (95% CI 0.58–0.94) for total fracture

RR: 0.61 (95% CI 0.4–0.92) for hip fracture

8 RCTs, N = 68,957

Thanapluetiwong et al. (2020) [63]

26 RCTs

N = 40,209

Vit D ± calcium

Major populations were elderly women with age less than 80 years

Vit D alone failed to show any fracture lowering benefit, RR 0.949 (95% CI 0.846–1.064)

Vit D + calcium significantly lower fracture rates,

RR 0.859 (95% CI 0.741–0.996)

Li et al. (2021) [64]

33 RCTs

N = 83,083

Vit D ± calcium

No younger than 47 years old; Follow-up ranged from 3 to 84 months

Fracture cases confirmed with hospital diagnosis, medical records, or World Health Organization diagnostic criteria; subjects not treated with any osteoporosis medications and did not have any special physical training;

Vit D alone: no reduction of the risk of total fractures (RR 0.96 (95% CI 0.87–1.05)

Vit D3 (700–800 IU/d) + calcium: significant reduction of total (RR 0.85 (95% CI 0.77–0.95), hip (RR 0.81 (95% CI 0.68–0.97), and non-vertebral fractures (RR 0.84 (95% CI 0.74–0.95), in a pairwise meta-analysis

Chakhtoura et al. (2022) [65]

Umbrella review of meta-Analyses

25 RCTs

Vit D + calcium—13 SR/MAs

Mean age between 62 and 85 years

Vit D + calcium:

↓ risk of hip fractures in 8/12 SRs/MAs (RR 0.61–0.84)

Vit D alone—19 SR/MAs

Vit D dose 400–800 IU/day

Trials extended from 1 to 7 years

5 SRs/MAs reported on baseline 25(OH)D (20.9–83.8 nmol/L)

↓ risk of any fractures in 7/11 SRs/MAs (RR 0.74–0.95)

6 SR/MAs included 1 trial providing a high dose of 300,000 IU once

Calcium dose was 500–1200 mg/day

No fracture risk reduction in SRs/MAs exclusively evaluating community-dwelling individuals or in those on vit D alone compared to placebo/control

Kong et al. (2022) [66]

32 RCTs

N = 104,363

16 RCTs

N = 36.793 for fracture outcome

Vit D (median dose of 800 IU/d) ± calcium

8 studies reported < 800 IU/day

Most studies included women with 75% of participants (range 15–100%)

Vit D 800–1000 IU/d:

Pooled relative risk 0.87 (95% CI 0.78–0.97) for osteoporotic fractures

15 studies 800–1000 IU/day, and

Median age was 72 years (range 53–85)

No reduction of hip fractures RR 0.84 (95% CI 0.64–1.10

9 studies > 1000 IU/day

26 studies reported daily administration, while 6 reported intermittent administration

Median follow-up duration was 24 months (range 9–120)

Vit D 800 to 1000 IU/d + calcium:

pooled RR 0.88 (95% CI 0.78–1.00) for osteoporotic fractures

RCT randomized controlled trial, 25(OH)D 25-hydroxyvitamin D, Vit D vitamin D, RR relative risk, OR odds ratio

Bold: statistically significant differences