Is supplementation with calcium, vitamin D, or combined calcium and vitamin D associated with a lower fracture incidence in community-dwelling older adults?
In this meta-analysis of 33 randomized clinical trials that included 51 145 participants, the use of supplements that included calcium, vitamin D, or both was not associated with a significant difference in the risk of hip fractures compared with placebo or no treatment (risk ratio, 1.53, 1.21, and 1.09, respectively).
These findings do not support the routine use of these supplements in community-dwelling older adults.
The increased social and economic burdens for osteoporosis-related fractures worldwide make the prevention of such injuries a major public health goal. Previous studies have reached mixed conclusions regarding the association between calcium, vitamin D, or combined calcium and vitamin D supplements and fracture incidence in older adults.
To investigate whether calcium, vitamin D, or combined calcium and vitamin D supplements are associated with a lower fracture incidence in community-dwelling older adults.
The PubMed, Cochrane library, and EMBASE databases were systematically searched from the inception dates to December 24, 2016, using the keywords calcium, vitamin D, and fracture to identify systematic reviews or meta-analyses. The primary randomized clinical trials included in systematic reviews or meta-analyses were identified, and an additional search for recently published randomized trials was performed from July 16, 2012, to July 16, 2017.
Randomized clinical trials comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment for fracture incidence in community-dwelling adults older than 50 years.
Data Extraction and Synthesis
Two independent reviewers performed the data extraction and assessed study quality. A meta-analysis was performed to calculate risk ratios (RRs), absolute risk differences (ARDs), and 95% CIs using random-effects models.
Main Outcomes and Measures
Hip fracture was defined as the primary outcome. Secondary outcomes were nonvertebral fracture, vertebral fracture, and total fracture.
A total of 33 randomized trials involving 51 145 participants fulfilled the inclusion criteria. There was no significant association of calcium or vitamin D with risk of hip fracture compared with placebo or no treatment (calcium: RR, 1.53 [95% CI, 0.97 to 2.42]; ARD, 0.01 [95% CI, 0.00 to 0.01]; vitamin D: RR, 1.21 [95% CI, 0.99 to 1.47]; ARD, 0.00 [95% CI, −0.00 to 0.01]. There was no significant association of combined calcium and vitamin D with hip fracture compared with placebo or no treatment (RR, 1.09 [95% CI, 0.85 to 1.39]; ARD, 0.00 [95% CI, −0.00 to 0.00]). No significant associations were found between calcium, vitamin D, or combined calcium and vitamin D supplements and the incidence of nonvertebral, vertebral, or total fractures. Subgroup analyses showed that these results were generally consistent regardless of the calcium or vitamin D dose, sex, fracture history, dietary calcium intake, and baseline serum 25-hydroxyvitamin D concentration.
Conclusions and Relevance
In this meta-analysis of randomized clinical trials, the use of supplements that included calcium, vitamin D, or both compared with placebo or no treatment was not associated with a lower risk of fractures among community-dwelling older adults. These findings do not support the routine use of these supplements in community-dwelling older people.
Approximately 40% of 50-year-old women will have major osteoporotic fractures during the remainder of their lifetimes,1 and these fractures are associated with major morbidity.2 Hip fractures are generally considered the most serious type of osteoporotic fracture. A cohort study conducted between 2000 to 2010 showed that more than one-fifth of patients died within 1 year after hip fracture.3 Survivors may require greater social and nursing care.2 The increased social and economic burdens associated with osteoporosis-related fractures worldwide make their prevention a major public health goal.
Practice guidelines recommend calcium and vitamin D supplements for older people to prevent fractures in people with osteoporosis. However, meta-analyses published to date have not reached consistent conclusions regarding the association between calcium, vitamin D, or combined calcium and vitamin D supplements and fracture risk.4
Older people living in institutions such as nursing homes and residential care facilities have a higher risk of fracture compared with people living in the community.5 Therefore, the association of calcium and vitamin D supplementation with fracture risk may differ between community-dwelling men and women and people living in institutions. In addition, trials assessing calcium and vitamin D supplementation and risk of fracture have recently been published and add to the evidence base of the associations of calcium and vitamin D with fracture risk. Therefore, a systematic review and meta-analysis was performed to separately compare calcium, vitamin D, and combined calcium and vitamin D supplements with a placebo or no treatment for fracture incidence in community-dwelling older adults.
This meta-analysis was performed according to the Cochrane Handbook for Systematic Reviews of Interventions6 and presented based on Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines.7 The protocol for this meta-analysis is available in PROSPERO (CRD42016053867).
We searched the PubMed, Cochrane library, and EMBASE databases from the inception dates to December 24, 2016, using the keywords calcium, vitamin D, and fracture to identify published systematic reviews or meta-analyses evaluating the association between calcium, vitamin D, or combined calcium and vitamin D supplements and the incidence of fracture. There were no language restrictions, but the search was restricted to systematic reviews or meta-analyses published in the last 10 years from December 24, 2006, toDecember 24, 2016, and excluded systematic reviews or meta-analyses that included only populations living in institutions (detailed search strategies are reported in eTable 1 in the Supplement). We identified original randomized clinical trials (RCTs) included in the systematic reviews or meta-analyses. An additional search was performed to identify recently published RCTs (from July 16, 2012, to July 16, 2017) meeting inclusion criteria, using the databases and keywords described above.
Trials were selected based on the following inclusion criteria: (1) RCTs comparing calcium, vitamin D, or combined calcium and vitamin D supplements with a placebo or no treatment group; (2) trials enrolling adults older than 50 years and living in their communities; and (3) trials providing fracture data. Exclusion criteria were (1) randomized trials without a placebo or no treatment group; (2) trials of participants with corticosteroid-induced secondary osteoporosis; (3) trials in which supplementation with calcium, vitamin D, or combined calcium and vitamin D was combined with other treatments (eg, an antiosteoporotic drug); (4) trials in which vitamin D analogues (eg, calcitriol) or hydroxylated vitamin D were used; and (5) trials in which dietary intake of calcium or vitamin D (eg, from milk) was evaluated.
The methodological quality for the included RCTs was assessed independently by 2 researchers (J.-G.Z., L.L.) based on Cochrane risk-of-bias criteria,6 and each quality item was graded as low risk, high risk, or unclear risk. The 7 items used to evaluate bias in each trial included the randomization sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting, and other bias. We defined other bias as trials sponsored by drug companies and trials in which baseline characteristics were not similar between different intervention groups. The included trials were graded as low quality, high quality, or moderate quality based on the following criteria: (1) trials were considered low quality if either randomization or allocation concealment was assessed as a high risk of bias, regardless of the risk of other items; (2) trials were considered high quality when both randomization and allocation concealment were assessed as a low risk of bias, and all other items were assessed as low or unclear risk of bias in a trial; (3) trials were considered moderate quality if they did not meet criteria for high or low risk.
Two researchers (J.-G.Z., L.L.) independently extracted the following information from each study: lead author; publication year; country of origin; participant characteristics; doses of calcium, vitamin D, or their combination; dietary calcium intake; baseline serum 25-hydroxyvitamin D concentration; and trial duration. Disagreements were resolved by consensus. If the trials had more than 2 groups or factorial designs and permitted multiple comparisons, we extracted only the information and data of interest reported in the original articles. If a meta-analysis noted that unpublished data were provided by the primary authors, we extracted those fracture data from forest plots of the meta-analysis and reviewed original articles to confirm whether the trials met our inclusion criteria. When those data were our outcomes of interest, we pooled them with the data from primary trials.
The number of participants with hip fracture was the primary outcome because hip fracture can lead to more serious consequences than other fractures for older people. The secondary outcomes were the number of participants with nonvertebral fracture, vertebral fracture, and total fractures. Fractures were defined as total fractures when they occurred at all sites or when trials did not describe the sites of fractures in detail. If a trial only reported the number of participants with fractures at a single site, such as hip fracture, we did not consider it to be a total fracture.
The association of calcium, vitamin D, and combined calcium and vitamin D supplements with fracture incidence was assessed, and each type of supplement was separately compared with a placebo or no treatment group. We performed meta-analysis to calculate risk ratios (RRs), absolute risk differences (ARDs), and 95% CIs using the Mantel-Haenszel statistical method. If zero events were reported for one group in a comparison, a value of 0.5 was added to both groups for each such study. Based on the practice recommendation of the Cochrane Handbook,6 trials with zero events in both the intervention and the control groups were not included in the meta-analysis when RRs were calculated.
A random-effects model was used to pool the data, and statistical heterogeneity between summary data was evaluated using the I2 statistic. Sensitivity analysis was performed by excluding low-quality studies, trials recruiting participants with particular conditions, or trials with characteristics different from the others.
When an inconsistency was detected between the RR and ARD for the same outcome, we explained the results based on the RR because the RR model is more consistent than ARD, particularly for an intervention aimed at preventing an undesirable event.6,8
To evaluate whether the association between calcium, vitamin D, or combined calcium and vitamin D supplements and fractures was modified by clinical characteristics, we specified subgroups based on dose and frequency of calcium supplementation (≥1 or <1 g/d), vitamin D supplementation (≥800 IU/d; <800 IU/d; intermittent high-dose given as once every year; intermittent high-dose given as other frequencies, including once every 3 or 4 months and once every 1 week or month), or combined calcium and vitamin D supplementation; sex (women-only trials or trials that include both men and women); fracture history (participants with a history of fractures or other conditions, including participants with fracture history in trials in which not all participants had a history of fracture before the start of the trial, no previous fracture history, and missing fracture data); dietary calcium intake (≥900 or <900 mg/d); and baseline serum 25-hydroxyvitamin D concentration (≥20 or <20 ng/mL). Analysis was performed to assess whether the difference between the subgroups was statistically significant. We assessed publication bias by examining funnel plots when the number of trials reporting the primary outcomes was 10 or more.6
All meta-analyses were performed using Revman version 5.3 (Cochrane Collaboration). All tests were 2-tailed, and P < .05 was considered statistically significant.
Studies Retrieved and Characteristics
From the searches for systematic reviews or meta-analyses, 884 potentially eligible records were identified. Titles and abstracts of these records were screened for inclusion. Full texts of 87 records were read, and 21 met the inclusion criteria (Figure 1). Four systematic reviews or meta-analyses evaluated calcium supplementation with or without vitamin D for fracture prevention in older people.9-12 Seventeen systematic reviews or meta-analyses evaluated vitamin D with or without calcium for fracture incidence.13-31 Twenty-five RCTs met the inclusion criteria from 21 included systematic reviews or meta-analyses. eTables 2 and 3 in the Supplement summarize the RCTs included in the systematic reviews or meta-analyses.
The searches for recently published RCTs yielded 1441 records, and 53 full texts of these records were reviewed. Of these, 15 trials met inclusion criteria. After excluding duplicate trials, 33 RCTs32-64 involving 51 145 participants were ultimately included in this meta-analysis (Figure 1). Hansson et al41 did not report the residential status of participants, although a previous meta-analysis classified this status as community.12 The trial by Hansson et al41 was included, but a sensitivity analysis was performed that excluded that trial. Table 1 reports the characteristics of the included RCTs. We excluded 38 trials for the reasons listed in eTable 4 in the Supplement.
eFigures 1 and 2 in the Supplement show the assessment of the risk of bias. All studies were randomized; 25 were double-blind, placebo-controlled trials; 19 trials described an adequate random sequence generation process; and 13 trials described the methods used for allocation concealment. One trial40 was low quality, 6 were high quality,54,56,58,61,63,64 and the others were moderate quality. Inkovaara et al40 did not report whether the data represent the number of fractures or participants with fracture (3 fractures in the placebo group, 1 fracture in the calcium group, 1 fracture in the vitamin D group, and no fracture in the combined calcium and vitamin D group). The data were included, but a sensitivity analysis was performed that excluded that trial. We obtained unpublished data for 6 trials51,52,58,61,63,64 from a Cochrane review.26 Two included trials enrolled 222 participants,33,48 accounting for 0.4% of total participants, and reported that no fracture events occurred in their intervention and control groups during the follow-up period. Publication bias was not reported because the number of trials reporting hip fracture (primary outcome) was less than 10 for each comparison.
Calcium was administered as calcium carbonate in 14 trials33,35,40,44,47,51-56,58,60,62; calcium citrate in 3 trials46,48,57; calcium citrate malate in 2 trials45,49; a combination of bicarbonate, lactate, and gluconate in 1 trial41; in combination with lactate, gluconate, and carbonate in 1 trial42; and in unclear form in 1 trial.39 Vitamin D was administered as vitamin D3 in 23 trials and vitamin D2 in 2 trials52,59 (Table 1).
Calcium Supplementation and Fracture Risk
Fourteen trials compared calcium supplements with a placebo or no treatment. As shown in Figure 2, there was no significant association of calcium supplementation with hip fracture (RR, 1.53 [95% CI, 0.97 to 2.42]; ARD, 0.01 [95% CI, 0.00 to 0.01]). There was no statistically significant association of calcium supplementation with nonvertebral fractures (RR, 0.95 [95% CI, 0.82 to 1.11]; ARD, −0.01 [95% CI, −0.02 to 0.01]), vertebral fractures (RR, 0.83 [95% CI, 0.66 to 1.05]; ARD, −0.01 [95% CI, −0.03 to 0.01]), or total fractures (RR, 0.88 [95% CI, 0.75 to 1.03]; ARD, −0.02 [95% CI, −0.03 to −0.01]) compared with placebo or no treatment. Baron et al47 recruited only participants with a recent history of colorectal adenomas. A sensitivity analysis in which the trias by Baron et al,47 Inkovaara et al,40 and Hansson and Roos41 were excluded showed that the results did not change (eTable 5 in the Supplement). There was no significant association of calcium with fracture risk in subgroups for hip, nonvertebral, vertebral, and total fractures based on calcium dose, sex, fracture history, dietary calcium intake, or baseline serum 25-hydroxyvitamin D concentration (Table 2).
Vitamin D Supplementation and Fracture Risk
Seventeen trials compared vitamin D supplementation with a placebo or no treatment. Figure 3 shows the result of the traditional meta-analysis comparing vitamin D with a placebo or no treatment. There was no significant association of vitamin D with hip fracture (RR, 1.21 [95% CI, 0.99 to 1.47]; ARD, 0.00 [95% CI, −0.00 to 0.01]) or nonvertebral fractures (RR, 1.10 [95% CI, 1.00 to 1.21]; ARD, 0.01 [95% CI, −0.00 to 0.01]), compared with placebo or no treatment. There was no significant association of vitamin D with risk for vertebral fractures (RR, 0.97 [95% CI, 0.54 to 1.77]; ARD, 0.00 [95% CI, −0.00 to 0.01]), or total fractures (RR, 1.01 [95% CI, 0.87 to 1.17]; ARD, 0.00 [95% CI, −0.01 to 0.01]).
Mitri et al62 included only participants who had a high risk of diabetes; the TIDE trial32 included only people with type 2 diabetes and glycated hemoglobin concentration of 6.5% to 9.5% who were at risk of cardiovascular disease; the VitDISH trial64 enrolled only participants with isolated systolic hypertension; and the VitaDial trial34 included only people receiving hemodialysis (chronic kidney disease stage 5) with serum 25-hydroxyvitamin D levels less than 30 ng/mL. A sensitivity analysis was performed that separately excluded the TIDE trial,32 VitDISH trial,64 and VitaDial trial,34 as well as the trials by Mitri et al62 and Inkovaara et al,40 and the results remained unchanged (eTable 5 in the Supplement).
Table 3 summarizes results of subgroup analyses for vitamin D and the incidence of fracture. Vitamin D supplementation was associated with a significantly higher incidence of hip fracture in participants with baseline serum 25-hydroxyvitamin D concentrations of 20 ng/mL or greater (RR, 1.49 [95% CI, 1.03 to 2.17]; ARD, 0.00 [95% CI, −0.00 to 0.01]), but interaction term compared with people with serum 25-hydroxyvitamin D concentrations less than 20 ng/mL was not statistically significant. Intermittent high-dose vitamin D given once yearly was associated with a higher incidence of hip fracture (RR, 1.41 [95% CI, 1.02 to 1.96]; ARD, 0.00 [95% CI, 0.00 to 0.01]) (Table 3).
Combination Calcium and Vitamin D Supplementation and Fracture Risk
Thirteen trials compared results for participants receiving combination calcium and vitamin D supplementation vs placebo or no treatment. In the Women’s Health Initiative (WHI) trial,55 36 282 women were randomized into 1 of 4 groups: (1) calcium combined with vitamin D; (2) combined supplementation with calcium, vitamin D, and hormone therapy; (3) hormone therapy alone; or (4) placebo alone. In this meta-analysis, only the data of the participants who did not receive hormone therapy were pooled.65Figure 4 shows results of the meta-analysis. There was no significant association of combined calcium and vitamin D with hip fracture (RR, 1.09 [95% CI, 0.85 to 1.39]; ARD, 0.00 [95% CI, −0.00 to 0.00]), nonvertebral fracture (RR, 0.88 [95% CI, 0.75 to 1.03]; ARD, −0.01 [95% CI, −0.02 to 0.00]), vertebral fracture (RR, 0.63 [95% CI, 0.29 to 1.40]; ARD, −0.00 [95% CI, −0.00 to 0.00]), or total fractures (RR, 0.90 [95% CI, 0.78 to 1.04]; ARD, −0.01 [95% CI, −0.01 to 0.00]). The results of sensitivity analysis were not altered after excluding the trial by Inkovaara et al40 (eTable 5 in the Supplement).
The subgroup analysis did not show any significant differences within subgroups based on the dose of calcium or vitamin D, sex, fracture history, dietary calcium intake, and baseline serum 25-hydroxyvitamin D concentration (Table 4).
Results of this meta-analysis showed that calcium, calcium plus vitamin D, and vitamin D supplementation alone were not significantly associated with a lower incidence of hip, nonvertebral, vertebral, or total fractures in community-dwelling older adults. Sensitivity analyses that excluded low-quality trials and studies that exclusively enrolled patients with particular medical conditions did not alter these results. Furthermore, these results were generally consistent regardless of the dose of calcium or vitamin D, sex, fracture history, calcium intake, and baseline serum 25-hydroxyvitamin D concentration.
A meta-analysis by Tang et al10 reported that calcium supplementation was significantly associated with prevention of osteoporosis-related fractures. However, the report by Tang et al included 2 large-sample cluster trials66,67 and did not adjust for the number of participants, which might have increased the probability of smaller P values and narrower CIs between the intervention and control groups. Bolland et al12 reported that calcium supplementation was significantly associated with a lower incidence of total fracture in community-dwelling participants. Results reported here showed that calcium supplementation was not associated with a lower rate of hip fracture. In the current analyses, the point estimate regarding the association of calcium supplementation with hip fracture was increased, but it did not reach statistical significance. These results suggest the possibility of a significant association of calcium supplementation with increased fracture incidence, but the current analyses may have lacked statistical power to show this association. However, the reason for this association is unclear. Overall, results reported here suggest that calcium should not be routinely recommended for fracture prevention.
Prior analyses also reported favorable associations of high-dose (≥800 IU daily) vitamin D supplementation and fracture incidence.20,24 Bischoff-Ferrari et al24 found that supplementation with 800 IU or more of vitamin D per day was associated with lower rates of hip fracture and nonvertebral fractures in adults 65 years or older. However, their findings may have been influenced by inclusion of the trial by Chapuy et al,67 which only enrolled participants living in an institution. Another possible reason for differences in conclusions of earlier meta-analyses and the current meta-analysis is that more recently published trials reported neutral or harmful associations of vitamin D supplementation and fracture incidence. Results reported here showed that vitamin D was associated with a higher risk for hip fracture, but this finding did not reach statistical significance. This finding may be attributable to lack of statistical power in this meta-analysis.
Avenell et al26 performed a Cochrane review that concluded that combined supplementation might be associated with reduced incidence of hip fracture or total fractures. Bolland et al27 found that supplementation with combined calcium and vitamin D did not decrease the incidence of hip fracture or total fractures in community-dwelling individuals. In the current meta-analysis, data from the WHI trial were updated compared with prior reports.55 The WHI trials demonstrated a significant interaction of hormone therapy for the association of supplementation with combined calcium and vitamin D and risk of hip fracture (P = .01).65 Supplementation with combined calcium and vitamin D was associated with lower fracture risk in participants who were also taking hormone therapy. In contrast, supplementation with combined calcium and vitamin D had no benefit in women not assigned to hormone therapy.65 However, previously published meta-analyses did not exclude patients receiving hormone therapy. In results reported here, data were pooled for 7972 participants (4015 participants randomly received combined calcium and vitamin D, and 3957 participants randomly received placebo) who did not receive hormone therapy.
In the meta-analysis reported here, few included trials specifically enrolled participants with established osteoporosis, but some trials enrolled participants with risk factors for osteoporosis, such as lower serum 25-hydroxyvitamin D concentration, low dietary calcium intake, previous fracture, and postmenopausal status. A subgroup analysis based on adherence was not performed in this meta-analysis because the definition of adherence substantially differed between included trials. A previous trial reported that calcium and vitamin D supplements lowered fracture risk for individuals living in residential institutions.67 These populations are more likely to have osteoporosis because of their poorer mobility, infrequent sun exposure, and poorer diet. For these reasons it is possible that older people living in residential care communities may benefit from calcium or vitamin D supplements.5 In summary, benefits of calcium and vitamin D supplementation may differ between people living in the community and people living in residential institutions.
This study has several limitations. First, RCTs from 21 published systematic reviews and meta-analyses were identified, which might lead to the omission of trials meeting inclusion criteria. Second, some included trials did not test baseline serum 25-hydroxyvitamin D concentrations for all participants. The subgroup results might have been different if all individuals were tested. Third, some RCTs were of poor quality and, for example, used unclear allocation concealment. Fourth, the methods used to classify studies as high quality may have been relatively lenient, and other researchers may have selected different definitions for study quality.
In this meta-analysis of randomized clinical trials, the use of supplements that included calcium, vitamin D, or both compared with placebo or no treatment was not associated with a lower risk of fractures among community-dwelling older adults. These findings do not support the routine use of these supplements in community-dwelling older people.
Corresponding Author: Jia-Guo Zhao, MD, Department of Orthopaedic Surgery, Tianjin Hospital, No. 406 Jiefang South Rd, Hexi District, Tianjin 300211, China (email@example.com).
Accepted for Publication: November 21, 2017.
Correction: This article was corrected online on January 11, 2018, for omission of a word in the “Inclusion Criteria” section that affected meaning.
Author Contributions: Dr Zhao had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Drs Zhao and Zeng contributed equally to the work as first authors.
Concept and design: Zhao.
Acquisition, analysis, or interpretation of data: All authors.
Drafting of the manuscript: Zhao.
Critical revision of the manuscript for important intellectual content: All authors.
Statistical analysis: Zhao, Zeng, Wang.
Obtained funding: Zhao, Zeng, Wang.
Administrative, technical, or material support: All authors.
Supervision: Zhao, Zeng.
Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.
Funding/Support: This study was supported by the Tianjin Science and Technology Research Project (16ZLZXZF00220).
Role of the Funder/Sponsor: The Tianjin Science and Technology Research Project had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.
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