Table 4.
Comparison of individual trials included in traditional systematic reviews/meta-analysesa and reasons for exclusionb of trials by some systematic reviews/meta-analyses investigating any fracture risk with calcium and vitamin D supplementation
| Bergman et al (17) 2010 |
Gillespie et al (37) 2012 |
Avenell et al (15) 2014 |
Bolland et al (19) 2014 |
Weaver et al (29) 2016 |
Zhao et al (31) 2017 |
Hu et al (24) 2019 |
Yao et al (30) 2019 |
Eleni and Panagiotis (22) 2020 |
|
|---|---|---|---|---|---|---|---|---|---|
| Pooled RR | 0.95 (0.46-1.85) | 0.95 (0.9-0.99) | 0.92 (0.85-0.99) | 0.86 (0.75-0.98) | 0.94 (0.89-0.99) | 0.74 (0.58-0.94) | |||
| Institutionalized RR | 0.85 (0.74-0.98)c | 0.67 (0.52-0.88)d | 0.76 (0.62-0.92)e | ||||||
| Community RR | 0.83 (0.59 and 1.16) | 0.96 (0.91-1.01) | 0.95 (0.85-1.06) | 0.90 (0.78-1.04) | 0.89 (0.74-1.06)f | 0.96 (0.90-1.02) | |||
| AMSTAR Quality assessment | Critically low | Moderate | Moderate | Critically low | Critically low | Low | Critically low | Critically low | Critically low |
| Total fx definition | Any fx excluding hip and NV fx | Fall-related fx at any site | Any fx excluding hip, V, and NV fx | Any fx excluding hip fx | Any fx excluding hip fx | Any fx excluding hip, V, & NV fx | Any fx excluding hip and V fx | Any fx including hip fxg | Any fx excluding hip and wrist fx |
| Trials | |||||||||
| Chapuy (45) 1992 |
NA 80/1387 115/1403 NA |
Excluded institutionalized trials | 10.67% 255/1634 308/1636 0.83 (0.71-0.96) |
19% 255/1634 308/1636 NA |
NA 66/877 97/888 0.69 (0.51-0.93) |
Excluded institutionalized trials | Excluded institutionalized trials | 7.0 160/1634 215/1636 0.72 (0.58-0.89) |
11.1% 80/1387 110/1403 0.74 (0.56-0.97) |
| Chapuy (46) 2002 |
NA 70/393 30/190 NA |
Excluded institutionalized trials | 1.57% 69/389 34/194 1.01 (0.7-1.47) |
4% 69/389 34/194 NA |
No data on any fracture as per SR/MA definition | Excluded institutionalized trials | Excluded institutionalized trials | 1.6 70/393 35/190 0.96 (0.61-1.51) |
7.9% 27/393 21/190 0.62 (0.36-1.07) |
| Inkovaara (83) 1983 |
NA | Excluded trials not reporting fall outcome | “Unclear whether the data represent fractures or participants with fractures” | NA | NA | 0.2% 0/46 3/42 0.13 (0.01-2.46) |
NA | Excluded trials with total fx events < 10 | NA |
| Dawson-Hughes (47) 1997 |
Excluded trials including men | Excluded trials not reporting fall outcome | 0.87% 11/187 26/202 0.46 (0.23-0.9) |
1% 11/187 26/202 NA |
NA 11/170 26/148 0.37 (0.19-0.72) |
No data on any fracture as per SR/MA definition | No data on any fracture as per SR/MA definition | Excluded trials with < 500 participants | 6.5% 11/187 26/202 0.46 (0.23-0.90) |
| Larsen et al (43) 2004 |
NA | “The outcome is only ‘severe’ falls leading to acute hospital admission” | “no treatment group received vitamin D & calcium alone” | “It’s a cluster randomized controlled trial” | NA | “No treatment group received vitamin D and calcium alone” | NA | “Not randomized (cluster randomized factorial design)” | 12.3% 217/4957 270/2116 0.34 (0.29-0.41) |
| Avenell et al (40) 2004 |
Excluded trials including men | Excluded trials not reporting on fall outcome | 0.14% 2/35 4/35 0.5 (0.10-2.56) |
0.3% 3/35 5/35 NA |
“Doesn’t qualify as an RCT of Calcium and vitamin D” | 0.8% 2/35 4/35 0.5(0.10,2.56) |
NA 2/35 4/35 NA |
Excluded trials with < 500 participants | “It assessed the open trial design and not explicitly the combination of Ca & vitamin D” |
| Harwood et al (NoNOF) (42) 2004 |
Excluded trials on post–hip fracture | 1.5% NA NA 0.5 (0.16-1.56) |
0.23% 6/75 5/37 0.59 (0.19-1.81) |
0.5% 6/75 5/37 NA |
NA 3/29 5/35 0.72 (0.19-2.78) |
1.6% 6/75 5/37 0.59 (0.19-1.81) |
NA 6/75 5/37 NA |
Excluded trials with < 500 participants | 2.5% 3/39 5/37 0.57(0.15,2.22) |
| Grant et al (RECORD) (41) 2005 |
Excluded trials including men | 19.96% N = 5292h 1.02 (0.87-1.19) |
6.14% 165/1306 179/1332 0.94 (0.77-1.15) |
14% 179/1306 192/1332 NA |
NA 179/1306 192/1332 0.95 (0.79-1.15) |
52.6% 165/1306 179/1332 0.94 (0.77-1.15) |
NA 165/1306 179/1332 NA |
6.6% 179/1306 192/1332 0.94 (0.76-1.17) |
12.6% 387/2649 377/2643 1.02 (0.90-1.17) |
| Porthouse et al (44) 2005 |
NA 29/1321 38/1993 NA |
10.14% N = 3314h 1.01 (0.71-1.44) |
2.52% 58/1321 91/1993 0.96 (0.7-1.33) |
5% 58/1321 91/1993 NA |
NA 24/607 22/602 1.08 (0.61-1.91)i |
19.8% 58/1321 91/1993 0.96 (0.7-1.33) |
NA 58/1321 91/1993 NA |
2.8% 58/1321 91/1993 0.96 (0.69-1.34) |
10.6% 58/1321 91/1993 0.96 (0.70-1.33) |
| Jackson et al (WHI) (48) 2006 |
Excluded interventions incorporating hormone therapy | Excluded trials not reporting fall outcome | 74.96% 2102/18176 2158/18106 0.97 (0.92-1.03) |
49% 1921/18176 1961/18106 NA |
Used post hoc analysis by Prentice et al (50) instead | No data on any fracture per SR/MA definition | NA | 78.3% 2102/18176 2158/18106 0.97 (0.91-1.03) |
13.0% 2102/18176 2158/18106 0.97 (0.92-1.03) |
| Bischoff-Ferrari et al (84) 2006 |
NA | 3.75% N = 3890h 0.46 (0.23-0.91) |
NA | NA | NA | NA | NA | NA | NA |
| Bolton-Smith et al (85) 2007 |
NA | Excluded trials not reporting fall outcome | 0.07% 2/62 2/61 0.98 (0.14-6.76) |
0.2% 2/62 2/61 NA |
NA | No data on any fracture per SR/MA definition | NA | Excluded trials with < 500 participants | Excluded because “confounded by the use of vitamin K1 in the therapeutic regimen” |
| Salovaara et al (49) 2010 |
Beyond search period | 11.63% N = 3195h 0.89 (0.65-1.21) |
2.82% 71/1586 82/1609 0.88 (0.64-1.2) |
6% 78/1718 94/1714 NA |
NA 78/1586 94/1609 0.84 (0.63-1.13) |
23.9% 78/1718 94/1714 0.83 (0.62-1.11) |
NA 78/1718 94/1714 NA |
3.7% 86/1586 103/1609 0.84 (0.63-1.13) |
11.0% 78/1586 94/1609 0.84 (0.63-1.13) |
| Prentice et al (50) 2013 |
Beyond search period | Beyond search period | NA | NA | NA 405/7530 458/7801 0.92 (0.80-1.04) |
NA | NA | NA | 12.6% 405/7530 458/7801 0.92 (0.80-1.04) |
| Liu et al (52) 2015 |
Beyond search period | Beyond search period | Beyond search period | Beyond search period | NA | 0.4% 1/50 2/48 0.48 (0.04-5.12) |
NA 1/50 2/48 NA |
Excluded trials with < 500 participants | NA |
| Xue et al (51) 2017 |
Beyond search period | Beyond search period | Beyond search period | Beyond search period | Beyond search period | 0.7% 3/139 2/173 1.87 (0.32-11.02) |
NA 3/139 2/173 NA |
Excluded trials with < 500 participants | NA |
The trials by Chapuy et al (45, 46) are the only ones conducted in institutionalized populations. All the other trials are conducted in community-dwelling populations. Individual cells are filled with the following: Percentage is weight of each trial, number of fractures/treatment group, number of fractures/control group, and effect size estimate.
Abbreviations: AMSTAR-2, A MeaSurement Tool to Assess systematic Reviews 2; Ca, calcium; D, vitamin D; fx, fracture; MA, meta-analysis; NA, not available; NV, nonvertebral; RCT, randomized clinical trial; RR, relative risk; SR, systematic review; V, vertebral; WHI, Women’s Health Initiative.
a MAs not included in matrix: DIPART, 2010: individual participant data without details about individual RCTs (23); Tricco et al, 2017: Network MA without details about individual RCTs (39).
b Reasons for exclusion of some trials by systematic reviews/meta-analyses either as exactly reported or derived from inclusion/exclusion criteria.
c “The test for subgroup differences was not significant (P = .13).”
d Not a subgroup analysis; community and institutionalized were each analyzed separately.
e “P for heterogeneity: 0.02.”
f This RR is for high D (≥ 800 IU/day) + high Ca (≥ 800 mg/day) vs placebo. RR for low D (< 800 IU/day) + high Ca (≥ 800 mg/day) is 0.48 (0.04-5.16). RR for high D (≥ 800 IU/day) + low Ca (< 800 mg/day) is 1.87 (0.31-11.13).
g Any fracture is defined as an fx occurring at any site, but if an RCT reported only hip fx, these were also counted as any fx.
h Only total number available (number of events per treatment/control is not available).
i CI for equally allocated subgroup.