Indian J Med Res 158, July 2023, pp 5-16 Quick Response Code:

DOI: 10.4103/ijmr.ijmr_1946_21

Systematic Review

Role of calcium &/or vitamin D supplementation in preventing

osteoporotic fracture in the elderly: A systematic review & meta-
analysis

Kavin Khatri1, Manmeet Kaur2, Tanish Dhir4, Ankita Kankaria3 & Hobinder Arora5

Departments of 1Orthopaedics, 2Pathology & 3Community & Family Medicine, All India Institute of Medical
Sciences, Bathinda, 4Department of Nephrology, Dayanand Medical College & Hospital, Ludhiana &
5
Department of Community & Family Medicine, Guru Gobind Singh Medical College, Faridkot, Punjab, India

Received June 23, 2021

Background & objectives: Calcium and vitamin D, separately or in combination are usually prescribed
to prevent fragility fractures in elderly population. However, there are conflicting results regarding the
ideal dosage and overall efficacy obtained from randomized controlled trials (RCTs) conducted in the
past. The objective of this study was to assess the fracture risk with the administration of calcium or
vitamin D alone or in combination in elderly population (>60 yr).
Methods: PubMed, Cochrane and Embase databases were searched to identify the studies from inception
to February 2021 with keywords, ‘vitamin D’, ‘calcium’ and ‘fracture’ to identify RCTs. The trials
with comparing vitamin D, calcium or combination with either no medication or placebo were included
for final analyses. The data were extracted and the study quality was assessed by two reviewers. The
principal outcome measure was fractures around hip joint and secondary outcomes assessed were
vertebral and any other fracture.
Results: Eighteen RCTs were considered for the final analysis. Neither calcium nor vitamin D
supplementation was associated with risk of fractures around hip joint [risk ratio (RR) 1.56; 95%
confidence interval (CI), 0.91 to 2.69, I2=28%; P=0.11]. In addition, the combined administration of
calcium and vitamin D was also not associated with fractures around the hip joint in comparison to either
no treatment or placebo. The incidence of vertebral (RR 0.95; 95% CI, 0.82 to 1.10, I2=0%; P=0.49) or
any other fracture (RR 0.83; 95% CI 0.65 to 1.06, I2=0%; P=0.14) was not significantly associated with
the administration of calcium and vitamin D either individually or in combination. Further subgroup
analysis of the results did not vary with the dosage of calcium or vitamin D, dietary calcium intake sex,
or serum 25-hydroxyvitamin D levels.
Interpretation & conclusions: The present meta-analysis of RCTs on calcium, vitamin D or a combination
of the two in comparison to no treatment or placebo did not support the routine administration protocol of
calcium and vitamin D either alone or in combination to lower the risk of fractures in elderly population.

Key words 25-Hydroxyvitamin D - calcium - hip fracture - osteoporosis - risk - randomized controlled trials - vitamin D

© 2023 Indian Journal of Medical Research, published by Wolters Kluwer - Medknow for Director-General, Indian Council of Medical Research
5
6 INDIAN J MED RES, JULY 2023

With the rise in the elderly population worldwide, combination) supplementation on the incidence of
the incidence of osteoporotic fractures is increasing fractures in elderly individuals with a prior history
proportionately1. Reportedly, there is a probability of a fracture. In addition, clinicaltrials.gov was also
that approximately 50 per cent women and 20 per cent searched for any undergoing trials. The keywords
men aged 50 yr suffer an osteoporotic fracture in their searched were ‘calcium’, ‘vitamin D’, and ‘fracture’.
remaining lifetime2,3. Hip fracture is one among the most No restriction of language, date or publication status
serious types of fragility fractures with approximately was applied on the search. The bibliographic details
one third risk of death in the subsequent year4. The of all the included studies were searched manually
survivors require good nursing and social care which for any additional citations. In case of duplication
translates into a major social and economic burden5. of publication, the study with the entire data set was
Hence, the thrust should be on prevention of these excluded. The complete search strategy has been
fractures. Common practice is to recommend combined listed in the Supplementary Material.
calcium and vitamin D supplements to patients after an
Inclusion criteria: Randomized controlled trials (RCTs)
osteoporotic fracture to prevent chances of the same in
or meta-analyses comparing calcium, and vitamin D,
the future. Vitamin D is required for the maintenance
individually or in or combination administered either
of good musculoskeletal health as it promotes the
with placebo or no treatment were included in this
absorption of calcium, osteoid mineralization and
study. Furthermore, this studies included adults older
maintenance of muscle functions.
than 50 yr with a previous history of fracture.
Previous studies on the effect of calcium
Exclusion criteria: Studies without a treatment or
supplementation on bone density have demonstrated
placebo group, with individuals having glucocorticoid-
that there is no substantial increase in bone density
associated osteoporosis, employed co-administration of
beyond one year of calcium administration6,7.
calcium and, vitamin D individually or in combination
Moreover, the influx of calcium ions in the blood leads
with other treatment modalities like antiresorptive
to suppression in the parathyroid hormone levels, thus
medication or included of dietary supplementation of
affecting the cycle of bone resorption and formation8.
either calcium or vitamin D were excluded from this
Few observational studies in the past have also shown
study.
that there is no relationship between calcium intake
and risk of fracture9. The regions with low calcium Selection of study data and data extraction: All the
intake touching Asia and Africa have a lower incidence studies were independently screened for meeting
of fracture in comparison to Europe and North the study criteria using Rayyan web application11.
America. This phenomenon has been referred to as the In case of any disagreement regarding the inclusion
‘Calcium Paradox’. In published literature, there is no of the study, the matter was resolved by a third
consensus to support the use of either calcium alone author. The reviewers independently extracted the
or in combination with vitamin D to reduce the risk characteristics of the studies and outcome measures.
of subsequent fractures. Hence, this meta-analysis was The extraction form was developed as per Cochrane
planned to assess calcium and, vitamin D individually recommendations12. Any discrepancy between the data
or in combination administration of calcium and extracted twice was resolved by analysis of the full
vitamin D with placebo for fracture incidence in the text by all the reviewers. The patient characteristics,
elderly population. calcium and, vitamin D administered individually or
in combination, dicalcium intake, serum vitamin D
Material & Methods
levels, cases with a history of hip, vertebral or non-
This systematic review and meta-analysis was vertebral fracture along with the duration of the trial
performed as per the recommendations of the PRISMA were recorded.
statement10 and was registered in PROSPERO (CRD
Assessment of risk of bias: Cochrane Collaboration’s
42021218539).
tool was used to check for the quality of studies included
Search strategy: PubMed, EMBASE and for the meta-analysis13. Each study was checked for
COCHRANE databases were searched since random generation of sequence; reporting of selective
inception to February 2021, to collect information outcome; concealment of allocation; blinding of
on published trials for evaluating the association participants; incomplete outcome data; selective
between calcium and, vitamin D (individually or in outcome reporting and potential sources of bias like
 KHATRI et al: CALCIUM OR VITAMIN D SUPPLEMENTATION IN THE ELDERLY 7

Records identified through

Identification
database searching (n=1273)

Records after duplicates removed

(n=32)
Screening

Records screened Records excluded

(n=1241) (n=1195)

Full text articles excluded with reasons (n=32)

Eligibility

▪ Fractures not reported (n=18)

Full text articles assessed ▪ Placebo or no treatment group not included (n=7)
for eligibility ▪ Ongoing trials (n=3)
(n=50) ▪ Other treatment modalities included (n=2)
▪ Exercise included in intervention group (n=1)
▪ Trial not randomized (n=1)
Included

Studies included in
qualitative analysis
(n=18)

Fig. 1. PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) flow diagram for the study inclusion and exclusion
procedure.

conflicts of interest. The performance of each study mean differences with the inverse variance approach.
was checked for risk of bias and tabulated. The risk In case of no event in a group, the RR was estimated
of bias was categorized as low, medium and high risk. by adding 0.5 to each cell. The testing of heterogeneity
When either randomization or allocation concealment was carried out using Chi-squared test and quantified
was assessed as a high risk of bias regardless of using I2. In the case of I2>50 per cent, substantial
other items, the trials were considered as low quality. heterogeneity was considered. P<0.10 was considered
Similarly, when both randomization and allocation significant.
concealment was assessed as a low risk of bias and To evaluate the association of fracture with the
other items as low or unclear risk of bias, the trial was variables under interest, the subgroups were specified
considered as high quality. The trials which did not based on dosage with the frequency of calcium
meet high or low quality criteria were considered as supplementation, sex, dietary intake and baseline
moderate quality14,15. A study was labelled with low serum vitamin D levels. The subgroups were analyzed
risk of bias if six out of the seven chosen domains were to look for significant results (P<0.05). Funnel plots
found to be low risk12. were used to assess publication bias when the number
Statistical analysis: The incidence of fracture was of trials reporting the primary outcomes was ≥10.
assessed for association with calcium and, vitamin D, The statistical analyses were performed using Review
administration individually or in combination. Each Manager Software (Cochrane Collaboration, UK). The
component was also compared with a placebo or criteria mentioned in Cochrane Handbook were used to
treatment given in the studies. The meta-analysis was convert medians, standard errors and 95 per cent CI to
performed to obtain relative risk ratios, absolute risk means and standard deviations.
difference and 95% confidence interval. In cases where Results
relative risk and absolute risk difference lead to similar
Literature search: A total of 1273 articles were obtained
end result, the results of relative risk were taken into
in the initial search for published RCTs on the study
consideration, especially when an intervention was
topic. Of these, 32 duplicate articles were removed,
targeted to prevent an unwanted event16.
leaving 1241 for screening. After screening titles and
The random-effect model of derSimonian and abstracts, 46 full text articles remained for review and
Laird approach17 was used to estimate pooled RRs and 18 articles were included as per the criteria. Hence, a
 8

Table I. Characteristics of included randomized controlled trials and participants

Study Country Total number Male:female Intervention Comparator Mean Calcium intake Serum
of participants ratio age (yr) (mg/day) vitamin D
Hansson and Roos Sweden 50 0:50 1 g/d calcium (n=25) Placebo (n=25) 65.9 NA NA
et al18, 1987
Reid et al19, 1993 New Zealand 135 0:135 1 g/d calcium (n=25) Placebo (n=67) 58 750 37.5
20
Recker et al , 1996 United States 197 0:197 1.2 g/d calcium (n=135) Placebo (n=102) 73.5 434 25.5
Peacock et al21, 2000 United States 261 74:187 0.75 g/d (n=126) Placebo (n=102) 73.8 597 25
22
Avenell et al , 2004 United States 105 53:11 1 g/d calcium (n=35); No treatment 78 NA NA
800 IU/day (n=35)
Harwood et al23, 2004 United 75 0:75 3,000,000 IU single dose No treatment 80.5 NA 11.6
Kingdom (n=38) (n=37)
Porthouse et al24, 2005 United 3314 0:3314 1 g/d calcium (n=1321); No treatment 76.8 1080 NA
Kingdom 800 IU/day (n=1993)
Grant et al25, 2005 United 2643 402:2241 1 g/d calcium (n=1311); Placebo (n=1332) 77 NA 15.2
Kingdom 800 IU/day
Prince et al26, 2006 Australia 1460 0:1460 0.48 g/d calcium (n=730) Placebo (n=730) 75.2 915 31
27
Reid et al , 2006 New Zealand 1471 0:1471 1 g/d calcium (n=732) Placebo (n=739) 74.3 857 20.7
Jackson et al28, 2006 United States 7972 0:7972 1 g/d calcium (n=4015); Placebo (n=3957) 62.4 1151 18.9
400 IU/day
Smith et al29, 2007 United 9440 4354:5086 3,000,000 IU single dose Placebo (n=4713) 79.1 625 22.6
Kingdom (n=4727)
INDIAN J MED RES, JULY 2023

Sander’s et al30, 2010 Australia 2258 0:2258 5,000,000 IU every year Placebo (n=1127) 76.1 976 19.8
(n=1131)
Salvovaara et al31, 2010 Finland 3432 0:3432 1 g/d calcium (n=1718); No treatment 67.3 957 19.8
800 IU/day (n=1714)
Punthakee et al32, 2012 Canada 1221 722:499 1000 IU/day (n=607) Placebo (n=614) 66.6 NA NA
33
Hin et al , 2017 United 305 155:150 4000 IU/day (n=102); Placebo (n=101) 71.7 710 20.1
Kingdom 2000 IU/day (n=102)
Khaw et al34, 2017 New Zealand 5108 2969:2139 2,000,000 IU single dose Placebo (n=2550) 65.9 810 25.2
followed by 1,00,000
monthly (n=2558)
Xue et al35, 2017 China 312 0:312 0.6 g/d calcium (n=139); Placebo (n=173) 63.6 NA 30.8
800 IU/day
NA, not available
 KHATRI et al: CALCIUM OR VITAMIN D SUPPLEMENTATION IN THE ELDERLY 9

Calcium No treatment or placebo Weight Risk ratio Risk ratio

Study or Subgroup Events Total Events Total (%) M-H, random, 95% CI M-H, random, 95% CI
1.4.1 hip frcture
Reid et al19, 1993 0 68 2 67 0.2 0.20 [0.01, 4.03]
Avenell et al22, 2004 1 29 1 35 0.2 1.21 [0.08, 18.46]
Grant et al25, 2005 49 1311 41 1332 9.3 1.21 [0.81, 1.83]
Prince et al26, 2006 11 730 6 730 1.7 1.83 [0.68, 4.93]
Reid et al27, 2006 17 732 5 739 1.6 3.43 [1.27, 9.26]
Subtotal (95% CI) 2870 2903 13 1.56 [0.91, 2.69]
Total events 78 55
Heterogeneity Tau2 = 0.11; Chi2 = 5.53; df = 4 (P=0.24); I2 = 28%
Test for overall effect: Z = 1.60 (P=0.11)
1.4.2 vertebral factors
Reid et al19, 1993 2 68 6 67 0.7 0.33 [0.07, 1.57]
Peacock et al21, 2000 11 119 12 117 2.7 0.90 [0.41, 1.96]
Avenell et al22, 2004 4 29 3 35 0.8 1.61 [0.39, 6.62]
Grant et al25, 2005 163 1311 178 1332 33.2 0.93 [0.76, 1.13]
Reid et al27, 2006 107 732 109 739 23.1 0.99 [0.77, 1.27]
Subtotal (95% CI) 2259 2290 60.5 0.95 [0.82, 1.10]
Total events 287 308
Heterogeneity Tau2 = 0.00; Chi2 = 2.48; df = 4 (P=0.65); I2 = 0%
Test for overall effect: Z = 0.70 (P=0.49)

1.4.3 other factors

Hansson and Ross18, 1987 1 25 1 25 0.2 1.00 [0.07, 15.12]
Reid et al19, 1993 0 68 1 67 0.2 0.33 [0.01, 7.92]
Recker et al20, 1996 27 95 34 102 8.7 0.85 [0.56, 1.30]
Peacock et al21, 2000 7 126 13 135 2.1 0.58 [0.24, 1.40]
Avenell et al22, 2004 0 29 1 35 0.2 0.40 [0.02, 9.46]
Grant et al25, 2005 3 1311 1 1332 0.3 3.05 [0.32, 29.26]
Reid et al27, 2006 27 730 38 739 6.7 0.72 [0.44, 1.17]
Prince et al26, 2006 38 730 39 730 8.2 0.97 [0.63, 1.51]
Subtotal (95% CI) 3114 3165 26.6 0.83 [0.65, 1.06]
Total events 103 128
Heterogeneity Tau2 = 0.00; Chi2 = 3.34; df = 7 (P=0.85); I2 = 0%
Test for overall effect: Z = 1.49 (P=0.14)

Total (95% CI) 8358 100 0.96 [0.85, 1.10]

Totsl events 468
Heterogeneity Tau2 = 0.00; Chi2 = 17.54; df = 17 (P=0.42); I2 = 3%
Test for overall effect: Z = 0.55 (P=0.58) 0.01 0.1 1 10 100
Test for subgroup differences: Chi2 = 4.32; df = 2 (P=0.12); I2 = 53.7% Favours calcium Favours no treat/placebo

Fig. 2. Forrest plot of trials with administration of calcium for prevention of fracture in hip, vertebrae and other parts of the body.

total of 18 RCTs which involved 39759 participants Calcium intake and risk of fracture: Calcium was
were selected in this meta-analysis (Fig. 1). The administered in the form of calcium carbonate in ten
characteristics of the included RCTs are given in Table I trials, calcium citrate malate in two trials, calcium
and the list of excluded trials along with the reasons citrate in two trials; combination of bicarbonate,
have been provided in the Supplementary Table. lactate and, gluconate in one trial; lactate, gluconate,
The risk of bias of the studies included was assessed carbonate in two trials and unclear form in one trial. The
(Supplementary Figs 1 and 2). Egger’s linear regression association between calcium administration and hip
analysis was used for the evaluation of publication bias fracture [risk ratio (RR) 1.56; 95% confidence interval
for the primary outcome measure and no publication (CI), 0.91 to 2.69, I2=28%; P=0.11], vertebral fracture
bias was noted (P=0.901; Supplementary Fig. 3). (RR 0.95; 95% CI, 0.82 to 1.10, I2=0%; P=0.49) or
10 INDIAN J MED RES, JULY 2023

Table II. Subgroup analysis for calcium administration and fracture risk prevention in each factor
Factor Participants Total number RR (95% CI) P
with fracture of participants
Hip fracture
Dose of calcium
<1 g 17 1460 1.83 (0.68‑4.93) 0.76
>1 g 116 4313 1.51 (0.67‑3.37)
Sex
Women only 41 3066 1.97 (0.74‑5.28) 0.31
Both sex 92 2707 1.21 (0.81‑1.82)
Serum 25(OH)D levels at presentation
>20 ng/ml 41 3066 1.97 (0.74‑5.28) 0.16
<20 ng/ml 92 2707 1.21 (0.81‑1.82)
Vertebral fracture
Dose of calcium
>1 g 572 4313 0.95 (0.82‑1.11) 0.63
<1 g 23 236 0.90 (0.41‑1.96)
Sex
Women only 224 1606 0.76 (0.30‑1.92) 0.94
Both sex 371 2943 0.94 (0.78‑1.13)
Serum 25(OH)D levels at presentation
>20 ng/ml 247 1842 0.96 (0.76‑1.21) 0.76
<20 ng/ml 341 2643 0.93 (0.76‑1.13)
Other fracture
Dose of calcium
>1 g 158 1918 0.87 (0.65‑1.15) 0.56
<1 g 73 4361 0.75 (0.47‑1.18)
Sex
Women only 204 3261 0.85 (0.66‑1.09) 0.97
Both sex 28 3153 0.68 (0.32‑1.44)
Serum 25(OH)D levels at presentation
>20 ng/ml 143 3064 0.84 (0.61‑1.16) 0.84
<20 ng/ml 85 3101 0.82 (0.57‑1.20)
25(OH)D, 25-hydroxy vitamin D; CI, confidence interval; RR, relative risk

other fractures (RR 0.83; 95% CI 0.65 to 1.06, I2=0%; vertebral fracture (RR, 1.28; 95% CI, 0.80 to 2.05,
P=0.14) was not significant (Fig. 2) in comparison I2=0%; P=0.31), hip fracture (RR, 1.18; 95% CI,
to either no treatment or placebo administration. The 0.91 to 1.53, I2=0%; P=0.21), or other fracture (RR,
subgroup analysis was carried out for the assessment 1.09; 95% CI, 0.94 to 1.20, I2=0%; P=0.11; Fig. 3)
of fracture risk in the hip, vertebra and other parts was not found to be significant. The subgroup analysis
of the body, but there was no significant association
for different dosage and frequency of assessment
based on calcium dosage, sex and serum 25-hydroxy
vitamin D [25OH)D] levels (Table II). of fracture risk was not found to be significantly
associated (Table III).
Vitamin D intake and risk of fracture: Vitamin D
supplementation with a placebo or no treatment Combined vitamin D and Calcium administration
was compared in six trials. The association between and fracture risk: Supplementation of calcium and
 KHATRI et al: CALCIUM OR VITAMIN D SUPPLEMENTATION IN THE ELDERLY 11

Vitamin D No treatment or placebo Weight Risk ratio Risks ratio

Study or Subgroup Events Total Events Total (%) M-H, random, 95% CI M-H, random, 95% CI
1.1.1 hip frcture
Avenell et al22, 2004 0 35 1 35 0.1 0.33 [0.01, 7.91]
Harwood et al23, 2004 0 38 1 37 0.1 0.32 [0.01, 7.73]
Grant et al25, 2005 47 1343 41 1332 6.7 1.14 [0.75, 1.72]
Smith et al29, 2007 55 4727 44 4713 7.4 1.25 [0.84, 1.85]
Sanders et al30, 2010 19 1131 15 1127 2.5 1.26 [0.64, 2.47]
Subtotal (95% CI) 7274 7244 16.9 1.18 [0.91, 1.53]
Total events 121 102
Heterogeneity Tau = 0.00; Chi = 1.39; df = 4 (P=0.85); I2 = 0%
2 2

Test for overall effect: Z = 1.26 (P=0.21)

1.1.2 vertebral factors
Avenell et al22, 2004 0 35 1 35 0.1 0.33 [0.01, 7.91]
Grant et al25, 2005 4 1343 1 1332 0.2 3.97 [0.44, 35.45]
Sanders et al30, 2010 35 1131 28 1127 4.8 1.25 [0.76, 2.03]
Subtotal (95% CI) 2509 2494 5.1 1.28 [0.80, 2.05]
Total events 39 30
Heterogeneity Tau2 = 0.00; Chi2 = 1,73; df = 2 (P=0.42); I2 = 0%
Test for overall effect: Z = 1.01 (P=0.31)
1.1.3 other factors
Avenell et al22, 2004 3 35 3 35 0.5 1.00 [0.22, 4.62]
Grant et al25, 2005 165 1343 178 1332 29.3 0.92 [0.75, 1.12]
Smith et al29, 2007 55 4727 44 4713 7.4 1.25 [0.84, 1.85]
Sanders et al , 2010
30
124 1131 101 1127 18.4 1.22 [0.95, 1.57]
Hin et al33, 2017 6 204 1 101 0.3 2.97 [0.36, 24.34]
Khaw et al34, 2017 146 2558 136 2550 22.2 1.07 [0.85, 1.34]
Subtotal (95% CI) 9998 9858 78 1.06 [0.94, 1.20]
Total events 499 463
Heterogeneity Tau2 = 0.00; Chi2 = 4.85; df = 5 (P=0.43); I2 = 0%
Test for overall effect: Z = 0.97 (P=0.33)

Total (95% CI) 19781 19596 100 1.09 [0.98, 1.21]

Total events
Heterogeneity Tau2 = 0.00; Chi2 = 8.96; df = 13 (P=0.78); I2 = 0% 0.01
0.01
0.0 0.1
0..11 1 10
10 100
10
00
Test for overall effect: Z = 1.60 (P=0.11) 0.01 0.1 1 10 100
Test for subgroup differences: Chi2 =0.98; df = 2 (P=0.61); I2 = 0% Favours vitamin D Favours no treat/placebo

Fig. 3. Forrest plot of trials with the administration of vitamin D for prevention of fracture in hip, vertebrae and other parts of the body.

vitamin D combined versus placebo or no treatment lower the chances of hip, vertebral or any other
was compared in seven trials. The association between fragility fractures in the elderly population. The
vertebral fracture (RR, 0.63; 95% CI, 0.29 to 1.40, exclusion of low-quality trials and trials with patients
I2=0%; P=0.26), hip fracture (RR, 1.10; 95% CI, 0.86 using specific medication did not affect the results.
to 1.40, I2=0%; P=0.47) and other fractures (RR, 0.921; The outcome was independent of calcium, vitamin D
95% CI, 0.78 to 1.08, I2=0%; P=0.29; Fig. 4) was dosage or the combination of two, sex and serum
not found to be significant. There was no significant 25(OH)D levels.
difference in the subgroup analysis based on intake of
calcium and vitamin D, sex, baseline 25(OH)D levels Prior meta-analysis carried out by Tang et
and dietary intake of calcium (Table IV). al had reported decrease in fragility fractures
36

with calcium supplementation. However, they had

Discussion included two cluster trials15,16 with a large sample
The meta-analysis revealed that calcium and, size and did not adjust for the cases which could
vitamin D individually or in combination did not have increased the chance of achieving low P value
12 INDIAN J MED RES, JULY 2023

Table III. Subgroup analysis for vitamin D administration and fracture risk prevention in each factor
Factor Participants Total RR (95% CI) P
with fracture number of
participants
Hip fracture
Frequency of vitamin D supplementation
Low daily dose 89 2745 1.11 (0.74‑1.68) 0.17
High dose once yearly 35 2333 1.19 (0.62‑2.3)
High dose intermittently 99 9440 1.25 (0.84‑1.85)
Sex
Women only 34 2258 1.26 (0.64‑2.47) 0.52
Both sex 89 2745 1.11 (0.74‑1.68)
Serum 25(OH)D levels at presentation
>20 ng/ml 222 14,448 1.19 (0.92‑1.55) NA
<20 ng/ml 0 0 NA
Vertebral fracture
Frequency of vitamin D supplementation
Low daily dose 6 2745 1.51 (0.14‑16.14) 0.21
Intermittent high dose 63 2258 1.25 (0.76‑2.03)
Sex
Women only 63 2258 1.25 (0.76‑2.03) 0.49
Both sex 6 2745 1.51 (0.14‑16.14)
Serum 25(OH)D levels at presentation
>20 ng/ml 0 0 NA NA
<20 ng/ml 69 5003 1.28 (0.80‑2.05)
Other fracture
Frequency of vitamin D supplementation
Low daily dose 349 2745 0.92 (0.76‑1.12) 0.23
High dose once yearly 225 2258 1.22 (0.95‑1.57)
High dose intermittently 282 5108 1.07 (0.85‑1.34)
Sex
Women only 225 2258 1.22 (0.95‑1.57) 0.56
Both sex 730 17,293 1.01 (0.88‑1.16)
Serum 25(OH)D levels at presentation
>20 ng/ml 955 19551 1.09 (0.98‑1.21) NA
<20 ng/ml 0 0 NA
CI, confidence interval; NA, not available; RR, relative risk

and narrow confidence intervals in the comparison be a routine recommendation for lowering risk of
groups. In another meta-analysis by Bolland et al9, fracture.
the dietary intake of calcium did not decrease the A meta-analysis by Bischoff-Ferrari et al37 had
risk of fracture, and role of calcium supplementation reported lower chances of hip fracture and other
in the prevention of fracture was also doubtful. In fragility fractures with the use of a high dose of
the present study, no association between calcium vitamin D (≥800 IU) per day. The inclusion of
supplementation and the risk of fracture was institutional patients by Chapuy et al38 in the meta-
observed. Hence, calcium supplementation need not analysis could have affected the finding of the meta-
 KHATRI et al: CALCIUM OR VITAMIN D SUPPLEMENTATION IN THE ELDERLY 13

Calcium with Vitamin D No treatment or placebo Weight Risk ratio Risks ratio
Study or Subgroup Events Total Events Total (%) M-H, random, 95% CI M-H, random, 95% CI
1.2.1 hip fracture
Avenell et al22, 2004 1 35 1 35 0.2 1.00 [0.07, 15.36]
Harwood et al23, 2004 1 75 1 37 0.2 0.49 [0.03, 7.67]
Porthouse et al24, 2005 8 1321 17 1993 2.6 0.71 [0.31, 1.64]
Grant et al25, 2005 46 1306 41 1332 10.5 1.14 [0.76, 1.73]
Jackson et al28, 2006 70 4015 61 3957 15.5 1.13 [0.80, 1.59]
Salvovaara et al31, 2010 4 1718 2 1714 0.6 2.00 [0.37, 10.88]
Subtotal (95% CI) 8470 9068 29.6 1.10 [0.86, 1.40]
Total events 130 123
Heterogeneity Tau2 = 0.00; Chi2 = 1.92; df = 5 (P=0.86); I2 = 0%
Test for overall effect: Z = 0.73 (P=0.47)

1.2.2 vertebral factors

Avenell et al22, 2004 0 35 1 35 0.2 0.33 [0.01, 7.91]
Grant et al25, 2005 0 1306 1 1332 0.2 0.34 [0.01, 8.34]
Jackson et al28, 2006 9 1718 13 1714 2.5 0.69 [0.30, 1.61]
Subtotal (95% CI) 3059 3081 2.9 0.63 [0.29, 1.40]
Total events 9 15
Heterogeneity Tau2 = 0.00; Chi2 = 0.34; df = 2 (P=0.84); I2 = 0%
Test for overall effect: Z = 1.14 (P=0.26)
1.2.3 other factors
Harwood et al23, 2004 6 75 5 37 1.4 0.59 [0.19, 1.81]
Avenell et al22, 2004 2 35 3 35 0.6 0.67 [0.12, 3.75]
Grant et al25, 2005 165 1306 178 1332 45.9 0.95 [0.78, 1.15]
Smith et al29, 2007 2 62 44 61 0.5 0.98 [0.14, 6.76]
Salvovaara et al31, 2010 71 1718 101 1714 18.6 0.86 [0.63, 1.18]
Xue et al33, 2017 3 139 1 173 0.6 1.87 [0.32, 11.02]
Subtotal (95% CI) 3335 3352 67.6 0.92 [0.78, 1.08]
Total events 249 463
Heterogeneity Tau2 = 0.00; Chi2 = 1.57; df = 5 (P=0.90); I2 = 0%
Test for overall effect: Z = 1.06 (P=0.29)

Total (95% CI) 14864 15501 100 0.96 [0.84, 1.09]

Total events
Heterogeneity Tau2 = 0.00; Chi2 = 6.32; df = 14 (P=0.96); I2 = 0%
Test for overall effect: Z = 0.67 (P=0.51) 0.01 0.1 1 10 100
Test for subgroup differences: Chi2 =2.49; df = 2 (P=0.29); I2 = 19.8% Favours calcium+vitamin D Favours no treat/placebo

Fig. 4. Forrest plot of trials with the combined administration of calcium and vitamin D for prevention of fracture in hip, vertebrae and other
parts of the body.

analysis. Other meta-analyses by Bergman et al39 reported no beneficial effect with the administration of
supported the use of a high dose of vitamin D to prevent calcium and vitamin D in combination in osteoporotic
the non-vertebral and non-hip fragility fractures. fractures. A meta-analysis by Zhao et al14 reported
However, they reported no significant association inconsistent results with a combined supplementation
between high dose vitamin D and hip fractures. In of calcium and vitamin D due to different inclusion
the present study, the reason for the difference in the criteria like the restriction of RCTs to community
result could be due to reporting of neutral or negative dwellers or residents of nursing homes.
association between vitamin D administration and risk
In a study by Jackson et al42, positive interaction
of fracture.
was reported between hormonal therapy and calcium
In a Cochrane review by Avenell et al40, the chance and vitamin D supplementation. They concluded
of hip fracture or combined fragility fracture was that a lower risk of fragility fractures with this
suggestively reduced with the combined administration combination was found in individuals on hormonal
of calcium and vitamin D. In contrast, Bolland et al41 therapy in contrast to the study group not on
14 INDIAN J MED RES, JULY 2023

Table IV. Subgroup analysis with combined calcium and vitamin D administration for fracture risk prevention
Factor Participants Total number RR (95% CI) P
with fracture of participants
Hip fracture
Combined calcium and vitamin D supplementation
Calcium with >1 g with low daily vitamin D 120 9454 1.07 (0.75‑1.54) 0.83
Other 133 8084 1.12 (0.80‑1.57)
Sex
Women only 164 14,830 1.07 (0.79‑1.46) 0.81
Both sex 89 2708 1.14 (0.76‑1.72)
Serum 25(OH)D levels at presentation
>20 ng/ml 0 0 NA NA
<20 ng/ml 251 17,468 1.10 (0.86‑1.4)
Vertebral fracture
Combined calcium and vitamin D supplementation
Calcium with >1 g with low daily vitamin D 2 2708 0.34 (0.04‑3.2) 0.67
Other 22 3432 0.69 (0.30‑1.61)
Sex
Women only 22 3432 0.69 (0.30‑1.61) 0.45
Both sex 2 2708 0.34 (0.04‑3.2)
Serum 25(OH)D levels at presentation
>20 ng/ml 0 0 NA NA
<20 ng/ml 24 6140 0.63 (0.29‑1.4)
Other fracture
Combined calcium and vitamin D supplementation
Calcium with >1 g with low daily vitamin D 512 6252 0.91 (0.77‑1.07) 0.53
Other 4 123 0.98 (0.14‑6.76)
Sex
Women only 15 235 0.67 (0.26‑1.77) 0.51
Both sex 501 14,988 0.92 (0.78‑1.08)
Serum 25(OH)D levels at presentation
>20 ng/ml 0 0 NA NA
<20 ng/ml 516 6375 0.91 (0.77‑1.07)
CI, confidence interval; NA, not available; RR, relative risk

hormonal therapy which did not report any reduction The present study did have a few limitations.
in fracture risk. In the present meta-analysis, all the First, some studies did not include the baseline values
cases on hormonal therapy were excluded from the of 25(OH)D levels which could have altered the
analysis. results of the subgroup analysis. Second, few RCTs
were of poor quality with allocation bias. Third,
The data from VITAL trial43 reported that vitamin D3 there are chances of publication bias in the results
supplementation did not reduced risk of fractures. reported by individual RCTs. Fourth, there could
There is a requirement of a large RCTs, especially have been variations in the classification of quality
in elderly high risk individuals involving combined of the studies.
administration of calcium and vitamin D to obtain a Overall, the present meta-analysis involving RCTs
reliable evidence. that included calcium and, vitamin D administered
 KHATRI et al: CALCIUM OR VITAMIN D SUPPLEMENTATION IN THE ELDERLY 15

individually or in combination compared with either 14. Zhao JG, Zeng XT, Wang J, Liu L. Association between
no treatment or placebo do not support their routine calcium or vitamin D supplementation and fracture incidence
in community-dwelling older adults: A systematic review and
supplementation in the elderly population. However,
meta-analysis. JAMA 2017; 318 : 2466-82.
the results of undergoing RCTs involving high doses
15. Luo D, Liu X, Du J, Liu J, Chen X, Zhou P, et al. Endoscopic
of vitamin D may have bearing on the future meta-
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analyses. pancreatitis: a systematic review and meta-analysis. Surg
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Conflicts of Interest: None. for meta-analysis of clinical trials with binary outcomes.
Stat Med 2002; 21 : 1575-600.
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For correspondence: Dr Manmeet Kaur, Department of Pathology, All India Institute of Medical Sciences, Mandi Dabwali Road,
Bathinda 151 001, Punjab, India
e-mail: puniamanmeet@gmail.com
Supplementary Fig. 1. Risk of bias table for included trials.
Supplementary Fig. 2. Risk of bias summary for included trials.

Supplementary Fig. 3. Funnel plot for publication Bias assessment.

 Supplementary Material
Search strategy in database
PUBMED:
#1 “calcium”[MeSH Terms] OR “calcium”[All Fields]
#2 “vitamin d”[MeSH Terms] OR “vitamin d”[All Fields] OR “ergocalciferols”[MeSH Terms] OR
“ergocalciferols”[All Fields]
#3 “fractures, bone”[MeSH Terms] OR (“fractures”[All Fields] AND “bone”[All Fields]) OR “bone
fractures”[All Fields] OR “fracture”[All Fields]
#4 trial”[Title/Abstract] OR “randomised trial”[Title/Abstract] OR “randomised controlled trial” [Title/Abstract]
#5 #1 or #2
#6 #3 and #5
#7 #4 and #6

EMBASE:
#1 ‘calcium’/exp OR calcium
#2 ‘vitamin d’/exp OR ‘vitamin d’
#3 ‘fracture’/exp OR fracture
#4 [cochrane review]/lim OR [systematic review]/lim OR [meta analysis]/lim
#5 #1 or #2
#6 #3 and 5
#7 #4 and #6
COCHRANE:
#1 calcium:ti,ab,kw
#2 vitamin d:ti,ab,kw
#3 fracture:ti,ab,kw
#4 #1 or #2
#5 #3 and #4
 Supplementary Table: List of excluded trials and reasons for the same
Trail excluded Year of publication Reason for exclusion
Inkovaara et al1 1983 Fracture data not reported
Lips et al 2
1996 Fracture data not reported
Dawson‑Hughes et al 3
1997 Fracture data not reported
Riggs et al4 1998 Fracture data not reported
Ruml et al 5
1998 Fracture data not reported
Baron et al6 1999 Fracture data not reported
Trivedi et al 7
2003 Fracture data not reported
Pfeifer et al8 2009 Trial did not include no treatment or placebo group
Bischoff‑Ferrari et al 9
2010 Trial did not include no treatment or placebo group
Witham et al 10
2010 Trial did not include no treatment or placebo group
Mitri et al11 2011 Fracture data not reported
Sambrook et al 12
2012 Trial included mandatory sunlight exposure in one of the groups
Schaller et al13 2012 Fracture data not reported
Rossini et al 14
2012 Trial is non‑randomized
Gendenneing et al15 2012 Fracture data not reported
Aloia et al 16
2013 Fracture data not reported
Witham et al17 2013 Fracture data not reported
Tella et al 18
2014 Placebo group not included
Takano et al 19
2014 Placebo or no treatment group not included
REVITAHIP trail et al20 2014 Placebo or no treatment group not included
Massart et al 21
2014 Fracture data not reported
Martineau et al22 2015 Fracture data not reported
Wang et al 23
2015 Multivitamin tablets were administered in the experimental group
Rolighed et al24 2015 Fracture data not reported
Uusi‑Rasi et al 25
2015 Fracture data not reported
Liu et al26
2015 Fracture data not reported
Schwetz et al27 2017 Fracture data not reported
Laiz et al 28
2017 Exercise was included in the intervention group
Pop et al29 2017 Placebo or no treatment group not included
Leblanc et al 30
2018 Ongoing trial
Joseph et al31 2018 Ongoing trial
DO‑HEALTH 32
2019 Ongoing trial

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