Role of calcium &/or vitamin D supplementation in preventing osteoporotic fracture in the elderly: A systematic review & meta-analysis

With the rise in the elderly population worldwide, the incidence of osteoporotic fractures is increasing proportionately1. Reportedly, there is a probability that approximately 50 per cent women and 20 per cent men aged 50 yr suffer an osteoporotic fracture in their remaining lifetime2,3. Hip fracture is one among the most serious types of fragility fractures with approximately one third risk of death in the subsequent year4. The survivors require good nursing and social care which translates into a major social and economic burden5. Hence, the thrust should be on prevention of these fractures. Common practice is to recommend combined calcium and vitamin D supplements to patients after an osteoporotic fracture to prevent chances of the same in the future. Vitamin D is required for the maintenance of good musculoskeletal health as it promotes the absorption of calcium, osteoid mineralization and maintenance of muscle functions.

Previous studies on the effect of calcium supplementation on bone density have demonstrated that there is no substantial increase in bone density beyond one year of calcium administration6,7. Moreover, the influx of calcium ions in the blood leads to suppression in the parathyroid hormone levels, thus affecting the cycle of bone resorption and formation8. Few observational studies in the past have also shown that there is no relationship between calcium intake and risk of fracture9. The regions with low calcium intake touching Asia and Africa have a lower incidence of fracture in comparison to Europe and North America. This phenomenon has been referred to as the ‘Calcium Paradox’. In published literature, there is no consensus to support the use of either calcium alone or in combination with vitamin D to reduce the risk of subsequent fractures. Hence, this meta-analysis was planned to assess calcium and, vitamin D individually or in combination administration of calcium and vitamin D with placebo for fracture incidence in the elderly population.

Material & Methods

This systematic review and meta-analysis was performed as per the recommendations of the PRISMA statement10 and was registered in PROSPERO (CRD 42021218539).

Search strategy: PubMed, EMBASE and COCHRANE databases were searched since inception to February 2021, to collect information on published trials for evaluating the association between calcium and, vitamin D (individually or in combination) supplementation on the incidence of fractures in elderly individuals with a prior history of a fracture. In addition, clinicaltrials.gov was also searched for any undergoing trials. The keywords searched were ‘calcium’, ‘vitamin D’, and ‘fracture’. No restriction of language, date or publication status was applied on the search. The bibliographic details of all the included studies were searched manually for any additional citations. In case of duplication of publication, the study with the entire data set was excluded. The complete search strategy has been listed in the Supplementary Material.

Inclusion criteria: Randomized controlled trials (RCTs) or meta-analyses comparing calcium, and vitamin D, individually or in or combination administered either with placebo or no treatment were included in this study. Furthermore, this studies included adults older than 50 yr with a previous history of fracture.

Exclusion criteria: Studies without a treatment or placebo group, with individuals having glucocorticoid-associated osteoporosis, employed co-administration of calcium and, vitamin D individually or in combination with other treatment modalities like antiresorptive medication or included of dietary supplementation of either calcium or vitamin D were excluded from this study.

Selection of study data and data extraction: All the studies were independently screened for meeting the study criteria using Rayyan web application11. In case of any disagreement regarding the inclusion of the study, the matter was resolved by a third author. The reviewers independently extracted the characteristics of the studies and outcome measures. The extraction form was developed as per Cochrane recommendations12. Any discrepancy between the data extracted twice was resolved by analysis of the full text by all the reviewers. The patient characteristics, calcium and, vitamin D administered individually or in combination, dicalcium intake, serum vitamin D levels, cases with a history of hip, vertebral or non-vertebral fracture along with the duration of the trial were recorded.

Assessment of risk of bias: Cochrane Collaboration’s tool was used to check for the quality of studies included for the meta-analysis13. Each study was checked for random generation of sequence; reporting of selective outcome; concealment of allocation; blinding of participants; incomplete outcome data; selective outcome reporting and potential sources of bias like conflicts of interest. The performance of each study was checked for risk of bias and tabulated. The risk of bias was categorized as low, medium and high risk. When either randomization or allocation concealment was assessed as a high risk of bias regardless of other items, the trials were considered as low quality. Similarly, when both randomization and allocation concealment was assessed as a low risk of bias and other items as low or unclear risk of bias, the trial was considered as high quality. The trials which did not meet high or low quality criteria were considered as moderate quality14,15. A study was labelled with low risk of bias if six out of the seven chosen domains were found to be low risk12.

Statistical analysis: The incidence of fracture was assessed for association with calcium and, vitamin D, administration individually or in combination. Each component was also compared with a placebo or treatment given in the studies. The meta-analysis was performed to obtain relative risk ratios, absolute risk difference and 95% confidence interval. In cases where relative risk and absolute risk difference lead to similar end result, the results of relative risk were taken into consideration, especially when an intervention was targeted to prevent an unwanted event16.

The random-effect model of derSimonian and Laird approach17 was used to estimate pooled RRs and mean differences with the inverse variance approach. In case of no event in a group, the RR was estimated by adding 0.5 to each cell. The testing of heterogeneity was carried out using Chi-squared test and quantified using I². In the case of I²>50 per cent, substantial heterogeneity was considered. P<0.10 was considered significant.

To evaluate the association of fracture with the variables under interest, the subgroups were specified based on dosage with the frequency of calcium supplementation, sex, dietary intake and baseline serum vitamin D levels. The subgroups were analyzed to look for significant results (P<0.05). Funnel plots were used to assess publication bias when the number of trials reporting the primary outcomes was ≥10. The statistical analyses were performed using Review Manager Software (Cochrane Collaboration, UK). The criteria mentioned in Cochrane Handbook were used to convert medians, standard errors and 95 per cent CI to means and standard deviations.

Results

Literature search: A total of 1273 articles were obtained in the initial search for published RCTs on the study topic. Of these, 32 duplicate articles were removed, leaving 1241 for screening. After screening titles and abstracts, 46 full text articles remained for review and 18 articles were included as per the criteria. Hence, a total of 18 RCTs which involved 39759 participants were selected in this meta-analysis (Fig. 1). The characteristics of the included RCTs are given in Table I and the list of excluded trials along with the reasons have been provided in the Supplementary Table.

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Fig. 1

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

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The risk of bias of the studies included was assessed (Supplementary Figs

Calcium intake and risk of fracture: Calcium was administered in the form of calcium carbonate in ten trials, calcium citrate malate in two trials, calcium citrate in two trials; combination of bicarbonate, lactate and, gluconate in one trial; lactate, gluconate, carbonate in two trials and unclear form in one trial. The association between calcium administration and hip fracture [risk ratio (RR) 1.56; 95% confidence interval (CI), 0.91 to 2.69, I²=28%; P=0.11], vertebral fracture (RR 0.95; 95% CI, 0.82 to 1.10, I²=0%; P=0.49) or other fractures (RR 0.83; 95% CI 0.65 to 1.06, I²=0%; P=0.14) was not significant (Fig. 2) in comparison to either no treatment or placebo administration. The subgroup analysis was carried out for the assessment of fracture risk in the hip, vertebra and other parts of the body, but there was no significant association based on calcium dosage, sex and serum 25-hydroxy vitamin D [25OH)D] levels (Table II).

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Fig. 2

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

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Vitamin D intake and risk of fracture: Vitamin D supplementation with a placebo or no treatment was compared in six trials. The association between vertebral fracture (RR, 1.28; 95% CI, 0.80 to 2.05, I²=0%; P=0.31), hip fracture (RR, 1.18; 95% CI, 0.91 to 1.53, I²=0%; P=0.21), or other fracture (RR, 1.09; 95% CI, 0.94 to 1.20, I²=0%; P=0.11; Fig. 3) was not found to be significant. The subgroup analysis for different dosage and frequency of assessment of fracture risk was not found to be significantly associated (Table III).

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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.

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Combined vitamin D and Calcium administration and fracture risk: Supplementation of calcium and vitamin D combined versus placebo or no treatment was compared in seven trials. The association between vertebral fracture (RR, 0.63; 95% CI, 0.29 to 1.40, I²=0%; P=0.26), hip fracture (RR, 1.10; 95% CI, 0.86 to 1.40, I²=0%; P=0.47) and other fractures (RR, 0.921; 95% CI, 0.78 to 1.08, I²=0%; P=0.29; Fig. 4) was not found to be significant. There was no significant difference in the subgroup analysis based on intake of calcium and vitamin D, sex, baseline 25(OH)D levels and dietary intake of calcium (Table IV).

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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.

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Discussion

The meta-analysis revealed that calcium and, vitamin D individually or in combination did not lower the chances of hip, vertebral or any other fragility fractures in the elderly population. The exclusion of low-quality trials and trials with patients using specific medication did not affect the results. The outcome was independent of calcium, vitamin D dosage or the combination of two, sex and serum 25(OH)D levels.

Prior meta-analysis carried out by Tang et al36 had reported decrease in fragility fractures with calcium supplementation. However, they had included two cluster trials15,16 with a large sample size and did not adjust for the cases which could have increased the chance of achieving low P value and narrow confidence intervals in the comparison groups. In another meta-analysis by Bolland et al9, the dietary intake of calcium did not decrease the risk of fracture, and role of calcium supplementation in the prevention of fracture was also doubtful. In the present study, no association between calcium supplementation and the risk of fracture was observed. Hence, calcium supplementation need not be a routine recommendation for lowering risk of fracture.

A meta-analysis by Bischoff-Ferrari et al37 had reported lower chances of hip fracture and other fragility fractures with the use of a high dose of vitamin D (≥800 IU) per day. The inclusion of institutional patients by Chapuy et al38 in the meta-analysis could have affected the finding of the meta-analysis. Other meta-analyses by Bergman et al39 supported the use of a high dose of vitamin D to prevent the non-vertebral and non-hip fragility fractures. However, they reported no significant association between high dose vitamin D and hip fractures. In the present study, the reason for the difference in the result could be due to reporting of neutral or negative association between vitamin D administration and risk of fracture.

In a Cochrane review by Avenell et al40, the chance of hip fracture or combined fragility fracture was suggestively reduced with the combined administration of calcium and vitamin D. In contrast, Bolland et al41 reported no beneficial effect with the administration of calcium and vitamin D in combination in osteoporotic fractures. A meta-analysis by Zhao et al14 reported inconsistent results with a combined supplementation of calcium and vitamin D due to different inclusion criteria like the restriction of RCTs to community dwellers or residents of nursing homes.

In a study by Jackson et al42, positive interaction was reported between hormonal therapy and calcium and vitamin D supplementation. They concluded that a lower risk of fragility fractures with this combination was found in individuals on hormonal therapy in contrast to the study group not on hormonal therapy which did not report any reduction in fracture risk. In the present meta-analysis, all the cases on hormonal therapy were excluded from the analysis.

The data from VITAL trial43 reported that vitamin D3 supplementation did not reduced risk of fractures.

There is a requirement of a large RCTs, especially in elderly high risk individuals involving combined administration of calcium and vitamin D to obtain a reliable evidence.

The present study did have a few limitations. First, some studies did not include the baseline values of 25(OH)D levels which could have altered the results of the subgroup analysis. Second, few RCTs were of poor quality with allocation bias. Third, there are chances of publication bias in the results reported by individual RCTs. Fourth, there could have been variations in the classification of quality of the studies.

Overall, the present meta-analysis involving RCTs that included calcium and, vitamin D administered individually or in combination compared with either no treatment or placebo do not support their routine supplementation in the elderly population. However, the results of undergoing RCTs involving high doses of vitamin D may have bearing on the future meta-analyses.