Association between vitamin D supplementation and fracture incidence in community-dwelling older adults: an updated systematic review and meta-analysis of randomized controlled trials

doi:10.21203/rs.3.rs-2253718/v1

Download PDF

Systematic Review

Association between vitamin D supplementation and fracture incidence in community-dwelling older adults: an updated systematic review and meta-analysis of randomized controlled trials

https://doi.org/10.21203/rs.3.rs-2253718/v1

This work is licensed under a CC BY 4.0 License

Version 1

posted

You are reading this latest preprint version

Previous studies have reached different conclusions regarding the effect of vitamin D supplementation and the incidence of fractures in the elderly. As more and more high-quality studies are published, an updated Meta-analysis is needed.

We searched the PubMed, Cochrane Library, Embase, and Web of Science databases (from creation date to September 10, 2022) using the keywords vitamin D and fracture. We also searched at https://clinicaltrials.gov/ to search for unpublished clinical studies. Randomized clinical trials comparing vitamin D supplements with a placebo or no treatment for fracture incidence in community-dwelling adults older than 50 years was included. Hip fracture was defined as the primary outcome. Secondary outcomes were total fracture, vertebral fracture, and nonvertebral fracture. The protocol is available in PROSPERO (ID: CRD42022360619).

A total of 15 randomized trials involving 53291 participants fulfilled the inclusion criteria. Supplementing with vitamin D had no significant effect on reducing the incidence of hip fracture (RR = 1.18, [95% CI, 0.99 − 0.41]), total fracture (RR = 1.01, [95% CI, 0.92–1.11]), vertebral fracture (RR = 0.97, [95% CI, 0.54–1.77]), or non-vertebral fracture (RR = 1.04, [95% CI, 0.97–1.12]). On the contrary, taking high doses of vitamin D once a year may increase the incidence of hip fractures (OR = 1.44, [95% CI, 1.03–2.02]). Besides, being in a low-light environment increased the incidence of hip fractures (OR = 1.25, [95% CI, 1.01–1.55]). There were no significant findings from subgroup analyses based on sex, fracture history, calcium consumption, baseline 25-hydroxyvitamin levels, or trial durations.

Vitamin D use in community-dwelling older adults does not reduce the risk of fracture. High doses of vitamin D at one-year intervals may even increase the risk of fracture. In addition, older adults in low sunlight exposure areas had a higher risk of fracture regardless of vitamin D use.

Fracture

Vitamin D

Older adult

It is widely recognized that vitamin D is crucial for bone health since it increases calcium absorption in the gut, encourages the mineralization of bone-like tissue, and controls calcium homeostasis and muscle function (1). In earlier longitudinal investigations, it was discovered that vitamin D insufficiency was linked to low bone mineral density and an increased risk of fracture (2). These studies indicate the potential benefit of vitamin D supplementation for fracture prevention because vitamin D insufficiency has also been linked to decreased muscle mass and strength (2, 3). As a result, current recommendations (4, 5) typically favor vitamin D supplementation as a means of preventing fractures in older persons.

Contrary to predictions, vitamin D supplementation has a mixed or indifferent impact on fracture risk (6, 7). Numerous studies (6, 8, 9) have found that taking vitamin D supplements lowers the incidence of fractures. Additionally, a recent meta-analysis has demonstrated that daily vitamin D administration lowers the risk of fracture (10). However, the effects of vitamin D therapy and placebo on fracture rates were not significantly different, according to a recently published RCT with 25,871 elderly community participants (11).

Previous studies, including randomized controlled trials and Meta-analyses, rarely discuss the effect of environmental factors (e.g., light) on trial outcomes for residents in the area where the trial was conducted. In addition, there is a different risk of fracture between middle-aged and older adults living in institutions with a higher burden of the underlying diseases and less outdoor activity compared with those living in the community. Therefore, separating study populations is needed to determine the exact relationship between vitamin D supplementation and fracture. This view is also reflected in a recently published systematic review (12), in which the authors concluded that the relationship between vitamin D supplementation and fracture may be biased by the inclusion of institutionalized residents. In a word, this updated systematic review focused on the effect of vitamin D supplementation on fracture risk in the community-dwelling population of middle-aged and older adults. Also, we considered some other possible factors to reach a more objective conclusion.

Indeed, the trial size, participants’ daily activities, amount of sunlight exposure, dietary status, and baseline vitamin D levels would influence the results. Furthermore, while doctors have a variety of options for vitamin D supplementation in terms of dose, dosing interval, and oral/injectable form, it is unclear if there is an adequate dose or dosing interval to lower the risk of fracture. In conclusion, it is still debatable if vitamin D administration can lessen the likelihood of fractures.

Thus, we performed a systematic review and meta-analysis update to evaluate the effects of vitamin D against placebo on the incidence of fractures in community-dwelling older individuals in order to consolidate the results of earlier studies and to identify the causes of these findings.

Overall Design

The Cochrane Handbook for Systematic Reviews of Interventions (13) was used to conduct this meta-analysis, and the Preferred Reporting Items for Systematic Reviews and Meta-analyses (14) were used to describe the results. The study protocol is available in PROSPERO (https://www.crd.york.ac.uk/PROSPERO/), protocol ID: CRD42022360619.

Search Trials

We searched the PubMed, Cochrane Library, Embase, and Web of Science databases (from creation date to September 10, 2022) using the keywords vitamin D and fracture to identify published original randomized controlled clinical trials assessing the relationship between vitamin D and fracture incidence (see Supplement Table 1 for detailed search strategy). Using the above keywords, we also searched at https://clinicaltrials.gov/ to search for unpublished clinical studies.

Inclusion and exclusion criteria

Trials were chosen based on the following criteria: (1) Randomized controlled trials contrasting vitamin D with a placebo group or no treatment group; (2) Trials enlisting persons over 50 years old and residing in their communities; (3) Trials providing information on fractures (hip fractures, total fractures, vertebral fractures, and nonvertebral fractures). Exclusion criteria: (1) trials with participants who had corticosteroid-induced secondary osteoporosis; (2) trials using calcium, or combining calcium and vitamin D supplementation; (3) trials using vitamin D analogs (such as osteopontin); (4) trials using hydroxylated vitamin D; (5) trials assessing dietary calcium or vitamin intake (e.g., milk).

Risk-of-Bias Assessments

Two researchers (Hengjia Tu and Yuzhuo Zhang) independently evaluated the methodological quality of the included RCTs using the Cochrane risk-of-bias criteria (13), grading each quality issue as low risk, high risk, or unclear risk. The randomization sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting, and other biases were used to assess the bias in each trial. Studies sponsored by pharmaceutical corporations and trials in which the baseline characteristics of the various intervention groups were not comparable were considered to be instances of other bias. Based on the following standards, the included trials were rated as low quality, high quality, or intermediate quality: (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 was 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.

Data Extraction

The following data were independently extracted from each study by three researchers (Hengjia Tu, Yuzhuo Zhang, and Zhixuan You): first author, date of publication, trial location, participant characteristics, vitamin D dosage, dietary calcium intake, initial serum 25-hydroxyvitamin D concentration, and duration of the trial. Conflicts were settled through consensus.

The primary outcome was the proportion of patients who had hip fractures since hip fractures in the elderly can have more serious outcomes than other fractures. The number of participants who sustained total fractures, vertebral fractures, and nonvertebral fractures were the secondary outcomes. All fracture data were provided by the enrolled studies, and fracture criteria were also mentioned in them. When the fracture site was not specifically described in the trial, it was deemed to be a total fracture. We did not consider a trial to have a total fracture if it simply listed the number of patients who had a single-site fracture, such as a hip fracture.

Statistical analysis

The association between vitamin D and fracture incidence was evaluated, and results were contrasted with those of the placebo and control groups. We used the Mantel-Haenszel statistical method to perform a meta-analysis, estimating risk ratios (RR) and 95% confidence intervals (CI).

The I² statistic was used to evaluate statistical heterogeneity among pooled data after data were obtained using a random effects model. I² values between 25% and 75% were judged to have some heterogeneity, I² values over 75% were regarded to have significant heterogeneity, and I² values below 25% were considered to have no heterogeneity. We conducted sensitivity analysis by eliminating low-quality papers when considerable heterogeneity was found.

Subgroup analysis

We defined subgroups based on clinical features to assess whether the relationship between vitamin D supplements and fractures was altered by these characteristics: 1. Research area (High sunlight exposure/ Low sunlight exposure), the division of sunlight intensity is roughly based on 45 degrees north/ south latitude; 2. Dose and frequency of 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); 3. Sex (women-only trials or trials that include both men and women); 4. 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); 5. Dietary calcium intake (≥ 900 or < 900 mg/d); 6. Baseline serum 25-hydroxyvitamin D concentration (≥ 20 or < 20 ng/mL). 7. Trial duration (≥ 1 Year or < 1 Year). The pointcuts were determined based on previously published meta-analyses (12, 15). 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(13).

Studies Retrieved and Characteristics

Figure 1 is the flow chart of literature selection. Table 1 lists the features of the included RCTs. The patients in 15 studies(8, 11, 16–28), which originated from eight different nations, had a mean age of > 50 years, with 24,080 men and 29,211 women. The control group received either a placebo or no therapy, whereas all experimental groups received vitamin D supplements at various frequencies and doses.

Risk of bias

The assessment of the bias is depicted in Fig. 2. All trials were randomized, and according to the evaluation criteria outlined in the method section, one low-quality study, seven high-quality studies, and seven studies of moderate quality were screened.

Vitamin D Supplementation and Fracture Risk

A vitamin D supplement was tested against a placebo or no treatment in fifteen trials. The result of the meta-analyses is depicted in Fig. 3–6. Supplementing with vitamin D had no significant effect on reducing the incidence of hip fracture (RR = 1.18, [95% CI, 0.99 − 0.41]), total fracture (RR = 1.01, [95% CI, 0.92–1.11]), vertebral fracture (RR = 0.97, [95% CI, 0.54–1.77]), or non-vertebral fracture (RR = 1.04, [95% CI, 0.97–1.12]). The funnel plot is symmetric (Fig. 7), suggesting little publication bias. Only people with type 2 diabetes who were also at high risk for cardiovascular disease were included in the TIDE trial and Mitri et al's study. When Mitri et al’s trial(22), the TIDE trial(24), and Inkovaara et al’s trial(16) were excluded from the sensitivity analysis, the findings did not change (Supplement Table 2).

Subgroup analyses

The findings of the subgroup analysis of vitamin D supplementation and fracture incidence are presented in Table 2. The studies were split into four groups based on how often and how many vitamins were used. According to the findings, taking high doses of vitamin D once a year may increase the incidence of hip fractures (OR = 1.44, [95% CI, 1.03–2.02]). However, it's important to note that this conclusion comes from just one study. Intermittent high-dose vitamin D usage (other frequencies), decreased fracture risk for all-cause fractures (OR = 0.76, [95% CI, 0.60–0.97]). In addition, we separated the study into groups with high and low levels of exposure to sunlight. Being in a low-light environment increased the incidence of hip fractures (OR = 1.25, [95% CI, 1.01–1.55]). There were no statistically significant findings from subgroup analyses based on sex, fracture history, calcium consumption, baseline 25-hydroxyvitamin levels, or trial durations. The results indicate that there is little connection between these variables and the association between vitamin D intake and fracture risk.

According to the findings of this meta-analysis, vitamin D supplementation was not substantially linked to a decrease in the frequency of hip, nonvertebral, vertebral, or total bone fractures among older people who live in their communities. Sensitivity analyses that removed subpar trials and studies that solely included people with particular medical conditions did not change these findings. As for subgroup analysis, to our surprise, once-yearly high-dose vitamin D use may increase the risk of fracture for hip fractures (OR = 1.44, [95% CI, 1.03–2.02]). Intermittent high-dose vitamin D use (other frequencies) decreased the incidence of total fractures (OR = 0.76, [95% CI, 0.60–0.97]), which was significantly different from other vitamin D use modalities (P = 0.03). Being in a region with limited light exposure increased the risk of fracture (OR = 1.25, [95% CI, 1.01–1.55]). Other subgroup analyses for other variables did not produce noteworthy outcomes.

The dose and frequency of vitamin D supplementation are currently controversial. Our findings indicate that whether supplementation is larger or less than 800 units of vitamin D per day, it has no appreciable impact on the frequency of hip, nonvertebral, vertebral, or total bone fractures. The second kind of therapy is high-dose intermittent vitamin D supplementation, which can be further divided into supplementation every year and supplementation with other frequencies (Table 2). In a UK study(8), 100 000 IU of vitamin D3 per four months for five years significantly decreased the relative risk of fracture in both men and women. Additionally, a study conducted in Australia(29) revealed that taking 500,000 IU of vitamin D orally per year increased the incidence of fractures in elderly women. Our findings support both of these claims. On the one hand, intermittent high-dose vitamin D use (other frequencies) lowers the risk of all-cause fracture (OR = 0.76, [95% CI, 0.60–0.97]), whereas once-yearly high-dose vitamin D usage raises the risk of hip fracture. This might be connected to how vitamin D is metabolized in the body(30). Since 25(OH)D has a half-life of roughly 15 days, changes at monthly or annual intervals are likely to occur, resulting in hazardous amounts of 25(OH)D in the blood(8, 10, 21). It has been demonstrated that a single high oral vitamin D dose can result in non-physiological fluctuation in blood 25-hydroxyvitamin D levels(31).

The results of this study differ from those of earlier meta-analyses(10, 15) for some reasons: First of all, no trials in this meta-analysis specifically sought out individuals with osteoporosis that had already developed. We only selected generally healthy older adults who lived in the community for our study. Because osteoporosis increases the risk of fracture, vitamin D supplementation may not be as effective at preventing fractures. Second, the biggest known sample size RCT(11) found a neutral correlation between vitamin D supplementation and fracture incidence, and its inclusion makes our meta-analysis more statistically valid. Additionally, we discovered that residing in an area with low light exposure increased the incidence of hip fractures (OR = 1.25, [95% CI, 1.01–1.55]) since this meta-analysis incorporated sunshine exposure in the subgroup analysis for the first time. This may support the advantages of light exposure for older persons living in general communities, where movement is more convenient than those residing in residential facilities. Contrarily, older people living in institutions may benefit from vitamin D supplementation, so it is important to take the population's living conditions and sun exposure into account when deciding whether to take a vitamin D supplement.

This study has some limitations. Firstly, we only looked at older people living in the community as a whole and did not investigate the importance of vitamin D supplementation for preventing fractures in older people residing in institutions. Secondly, several trials did not assess the individuals' baseline serum 25-hydroxyvitamin D concentrations, which might have had an impact on the outcomes of the subgroup analysis. Thirdly, in the subgroup analysis, the classification of light conditions is rough, based on the fact that annual solar radiation decreases with the increase of latitude, but ignores other factors that influence light, such as terrain and climate. Nonetheless, we think this classification is innovative. Finally, although the included RCT studies have advantages in population randomization and control of some bias factors, for outcome indicators such as fracture, the follow-up time is relatively too short. In the future, the relationship between vitamin D and fracture risk may need to be further explored with more long-term follow-up cohort studies.

In this study, we discovered that using vitamin D supplements did not significantly lower the frequency of hip, nonvertebral, vertebral, or total bone fractures. On the contrary, once-yearly high vitamin D dosages may increase the risk of hip fractures (OR = 1.44, 95% CI, 1.03–2.02). Also, higher fracture risk was found in areas with poor light exposure (OR = 1.25, 95% CI, 1.01–1.55), regardless of the form of vitamin D supplementation. However, intermittent high-dose vitamin D consumption may decrease the risk of total fracture (OR = 0.76, [95% CI, 0.60–0.97]). The findings suggest that there is uncertainty about vitamin D's effectiveness in preventing fractures in the general senior population, and that taking high doses of the vitamin once a year may be harmful. More research is needed to demonstrate the efficacy of vitamin D supplements in preventing fractures in different populations (adolescents, institutionalized middle-aged, and older adults).

Funding:

This work was supported by Special fund for scientific and technological innovation strategy of Guangdong Province in 2022 (Special Fund for Climbing Plan) [grant numbers pdjh2022a0581].

Acknowledgements:

None.

Holick MF. Vitamin D deficiency. New England Journal of Medicine. 2007;357(3):266–81.
Cauley JA, Greendale GA, Ruppert K, Lian Y, Randolph JF, Jr., Lo JC, et al. Serum 25 hydroxyvitamin D, bone mineral density and fracture risk across the menopause. J Clin Endocrinol Metab. 2015;100(5):2046–54.
Kuchuk NO, Pluijm SM, van Schoor NM, Looman CW, Smit JH, Lips P. Relationships of serum 25-hydroxyvitamin D to bone mineral density and serum parathyroid hormone and markers of bone turnover in older persons. J Clin Endocrinol Metab. 2009;94(4):1244–50.
Kahwati LC, LeBlanc E, Weber RP, Giger K, Clark R, Suvada K, et al. Screening for Vitamin D Deficiency in Adults: Updated Evidence Report and Systematic Review for the US Preventive Services Task Force. Jama. 2021;325(14):1443–63.
Appel LJ, Michos ED, Mitchell CM, Blackford AL, Sternberg AL, Miller ER, 3rd, et al. The Effects of Four Doses of Vitamin D Supplements on Falls in Older Adults: A Response-Adaptive, Randomized Clinical Trial. Ann Intern Med. 2021;174(2):145–56.
Holick MF, Binkley NC, Bischoff-Ferrari HA, Gordon CM, Hanley DA, Heaney RP, et al. Evaluation, Treatment, and Prevention of Vitamin D Deficiency: an Endocrine Society Clinical Practice Guideline. Journal of Clinical Endocrinology & Metabolism. 2011;96(7):1911–30.
Bolland MJ, Grey A. A case study of discordant overlapping meta-analyses: vitamin d supplements and fracture. PLoS One. 2014;9(12):e115934.
Trivedi DP, Doll R, Khaw KT. Effect of four monthly oral vitamin D3 (cholecalciferol) supplementation on fractures and mortality in men and women living in the community: randomised double blind controlled trial. BMJ (Clinical research ed). 2003;326(7387):469.
Ross AC, Manson JE, Abrams SA, Aloia JF, Brannon PM, Clinton SK, et al. The 2011 Report on Dietary Reference Intakes for Calcium and Vitamin D from the Institute of Medicine: What Clinicians Need to Know. Journal of Clinical Endocrinology & Metabolism. 2011;96(1):53–8.
Kong SH, Jang HN, Kim JH, Kim SW, Shin CS. Effect of Vitamin D Supplementation on Risk of Fractures and Falls According to Dosage and Interval: A Meta-Analysis. Endocrinol Metab (Seoul). 2022;37(2):344–58.
LeBoff MS, Chou SH, Ratliff KA, Cook NR, Khurana B, Kim E, et al. Supplemental Vitamin D and Incident Fractures in Midlife and Older Adults. N Engl J Med. 2022;387(4):299–309.
Chakhtoura M, Bacha DS, Gharios C, Ajjour S, Assaad M, Jabbour Y, et al. Vitamin D Supplementation and Fractures in Adults: A Systematic Umbrella Review of Meta-Analyses of Controlled Trials. J Clin Endocrinol Metab. 2022;107(3):882–98.
Cumpston M, Li T, Page MJ, Chandler J, Welch VA, Higgins JP, et al. Updated guidance for trusted systematic reviews: a new edition of the Cochrane Handbook for Systematic Reviews of Interventions. Cochrane Database Syst Rev. 2019;10:Ed000142.
Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gøtzsche PC, Ioannidis JP, et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. Bmj. 2009;339:b2700.
Zhao JG, Zeng XT, Wang J, Liu L. Association Between Calcium or Vitamin D Supplementation and Fracture Incidence in Community-Dwelling Older Adults: A Systematic Review and Meta-analysis. Jama. 2017;318(24):2466–82.
Inkovaara J, Gothoni G, Halttula R, Heikinheimo R, Tokola O. Calcium, vitamin D and anabolic steroid in treatment of aged bones: double-blind placebo-controlled long-term clinical trial. Age Ageing. 1983;12(2):124–30.
Lips P, Graafmans WC, Ooms ME, Bezemer PD, Bouter LM. Vitamin D supplementation and fracture incidence in elderly persons. A randomized, placebo-controlled clinical trial. Ann Intern Med. 1996;124(4):400–6.
Avenell A, Grant AM, McGee M, McPherson G, Campbell MK, McGee MA. The effects of an open design on trial participant recruitment, compliance and retention–a randomized controlled trial comparison with a blinded, placebo-controlled design. Clin Trials. 2004;1(6):490–8.
Grant AM, Avenell A, Campbell MK, McDonald AM, MacLennan GS, McPherson GC, et al. Oral vitamin D3 and calcium for secondary prevention of low-trauma fractures in elderly people (Randomised Evaluation of Calcium Or vitamin D, RECORD): a randomised placebo-controlled trial. Lancet. 2005;365(9471):1621–8.
Smith H, Anderson F, Raphael H, Maslin P, Crozier S, Cooper C. Effect of annual intramuscular vitamin D on fracture risk in elderly men and womena population-based, randomized, double-blind, placebo-controlled trial. Rheumatology. 2007;46(12):1852–7.
Sanders KM, Stuart AL, Williamson EJ, Simpson JA, Kotowicz MA, Young D, et al. Annual High-Dose Oral Vitamin D and Falls and Fractures in Older Women A Randomized Controlled Trial. Jama-Journal of the American Medical Association. 2010;303(18):1815–22.
Mitri J, Dawson-Hughes B, Hu FB, Pittas AG. Effects of vitamin D and calcium supplementation on pancreatic β cell function, insulin sensitivity, and glycemia in adults at high risk of diabetes: the Calcium and Vitamin D for Diabetes Mellitus (CaDDM) randomized controlled trial. Am J Clin Nutr. 2011;94(2):486–94.
Glendenning P, Zhu K, Inderjeeth C, Howat P, Lewis JR, Prince RL. Effects of three-monthly oral 150,000 IU cholecalciferol supplementation on falls, mobility, and muscle strength in older postmenopausal women: A randomized controlled trial. Journal of Bone and Mineral Research. 2012;27(1):170–6.
Punthakee Z, Bosch J, Dagenais G, Diaz R, Holman R, Probstfield J, et al. Design, history and results of the Thiazolidinedione Intervention with vitamin D Evaluation (TIDE) randomised controlled trial. Diabetologia. 2012;55(1):36–45.
Massart A, Debelle FD, Racapé J, Gervy C, Husson C, Dhaene M, et al. Biochemical parameters after cholecalciferol repletion in hemodialysis: results From the VitaDial randomized trial. Am J Kidney Dis. 2014;64(5):696–705.
Uusi-Rasi K, Patil R, Karinkanta S, Kannus P, Tokola K, Lamberg-Allardt C, et al. Exercise and Vitamin Din Fall Prevention Among Older Women A Randomized Clinical Trial. Jama Internal Medicine. 2015;175(5):703–11.
Hin H, Tomson J, Newman C, Kurien R, Lay M, Cox J, et al. Optimum dose of vitamin D for disease prevention in older people: BEST-D trial of vitamin D in primary care. Osteoporos Int. 2017;28(3):841–51.
Khaw KT, Stewart AW, Waayer D, Lawes CMM, Toop L, Camargo CA, et al. Effect of monthly high-dose vitamin D supplementation on falls and non-vertebral fractures: secondary and post-hoc outcomes from the randomised, double-blind, placebo-controlled ViDA trial. Lancet Diabetes & Endocrinology. 2017;5(6):438–47.
Sanders KM, Stuart AL, Williamson EJ, Simpson JA, Kotowicz MA, Young D, et al. Annual high-dose oral vitamin D and falls and fractures in older women: a randomized controlled trial. Jama. 2010;303(18):1815–22.
Chua GT, Wong RY. Association Between Vitamin D Dosing Regimen and Fall Prevention in Long-term Care Seniors. Canadian geriatrics journal: CGJ. 2011;14(4):93–9.
Hollis BW, Wagner CL. Clinical review: The role of the parent compound vitamin D with respect to metabolism and function: Why clinical dose intervals can affect clinical outcomes. J Clin Endocrinol Metab. 2013;98(12):4619–28.

Table 1

Characteristics of the Included Trials and Participants
Included Trials (Year)	Location	Men/Women	Mean age	Intervention (number)	Intervention Duration	Comparison (number)	Previous Fracture	Calcium Intake, mg/d	Baseline 25OHD, ng/ml
Inkovaara et al (1983)	Finland	16/71	79.6	1000 IU/d (n = 45)	9M	Placebo (n = 42)	NA	NA	NA
Lips et al (1996)	The Netherlands	662/1916	80	400 IU/d (n = 1291)	3-4y	Placebo (n = 1287)	No hip fracture	868	10.6^c
Trivedi et al (2003)	United Kingdom	2037/649	74.8	100 000 IU every 4M (n = 1345)	5y	Placebo (n = 1341)	NA	742	NA
Avenell et al (2004)	United Kingdom	12/58	78	800 IU/d (n = 35)	3.8y	No treatment (n = 35)	Yes	NA	NA
The RECORD Trial Group (2005)	United Kingdom	411/2264	77	800 IU/d (n = 1343)	2-5y	Placebo (n = 1332)	Yes	NA	15.2
Smith et al (2007)	United Kingdom	4354/5086	79.1	300 000 IU every year (n = 4727)	3y	Placebo (n = 4713)	Partial^a	625^b	22.6^c
Sanders et al (2010)	Australia	0/2258	76.1	500 000 IU every year (n = 1131)	3-5y	Placebo (n = 1127)	Partial^a	976	19.8^c
Mitri et al (2011)	United States	22/25	58	2000 IU/d (n = 23)	4M	Placebo (n = 24)	NA	926	25.3
Glendenning et al (2012)	Australia	0/686	76.7	150 000 IU every 3mo(n = 353)	9M	Placebo (n = 333)	NA	864	26.3
The TIDE Trial Investigators (2012)	Canada	622/499	66.6	1000 IU/d (n = 607)	4M	Placebo (n = 614)	Partial^a	NA	NA
Massart et al (2014)	Belgium	34/21	64.1	25 000 IU every week (n = 26)	3M	Placebo (n = 29)	NA	881	17.8
Uusi-Rasi et al (2015)	Finland	0/204	73.9	800 IU/d (n = 102)	2Y	Placebo (n = 102)	NA	1082	26.7
Hin et al (2017)	United Kingdom	155/150	71.7	4000 IU/d (n = 102); 2000 IU/d (n = 102)	1Y	Placebo (n = 101)	Partial^a	710	20.1
Khaw et al (2017)	New Zealand	2969/2139	65.9	200 000 IU followed by 100 000 IU monthly (n = 2558)	3.4Y	Placebo (n = 2550)	Partial^a	810^b	25.2
LeBoff et al (2022)	United States	12786/13085	67.1	2000 IU/d (n = 12927)	2-5Y	Placebo (n = 12944)	Partial^a	1200	30.7

Table 2

Subgroup Analysis of Association Between Vitamin D Supplementation and Fracture Incidence for Each Variable
Variable	No. of Trials	No. of Participants		Fracture, OR (95% CI)	P-Value
Variable	No. of Trials	Fracture	Total	Fracture, OR (95% CI)	P-Value
All Fracture
Research area					0.49
High sunlight exposure	4	1852	28862	1.02 [0.93, 1.12]
Low sunlight exposure	9	933	9881	0.96 [0.84, 1.10]
Vitamin D dose and frequency					0.03
≥ 800 IU/d	8	1955	30489	1.00 [0.91, 1.09]
< 800 IU/d	1	257	2578	1.12 [0.86, 1.44]
Intermittent high-dose (once every year)	1	280	2258	1.27 [0.99, 1.64]
Intermittent high-dose (other frequencies ^b)	3	293	3427	0.76 [0.60, 0.97]
Sex					0.07
Women-only trials	3	312	3148	1.23 [0.97, 1.56]
Trials with men and women	10	2473	35595	0.98 [0.90, 1.06]
Previous fractures					0.71
Yes	2	374	2745	1.04 [0.84, 1.29]
Other ^c	11	2411	35998	1.00 [0.92, 1.08]
Calcium intake, mg/d					0.48
≥ 900	4	1844	28380	1.02 [0.93, 1.12]
< 900	9	941	10363	0.96 [0.84, 1.10]
Baseline 25OHD, ng/mL					0.68
≥ 20	5	1591	27113	0.99 [0.89, 1.09]
< 20	8	1194	11630	1.02 [0.91, 1.15]
Trial Duration					0.29
< 1 Year	5	36	2097	0.71 [0.37, 1.36]
≥ 1 Year	8	2749	36647	1.01 [0.93, 1.09]
Hip Fracture
Research area					0.38
High sunlight exposure	3	148	28815	1.05 [0.76, 1.46]
Low sunlight exposure	6	349	17649	1.25 [1.01, 1.55]
Vitamin D dose and frequency					0.51
≥ 800 IU/d	4	204	28820	1.08 [0.82, 1.42]
< 800 IU/d	1	106	2578	1.21 [0.82, 1.79]
Intermittent high-dose (once every year)	2	144	11694	1.44 [1.03, 2.02]
Intermittent high-dose (other frequencies ^b)	2	43	3372	0.95 [0.52, 1.72]
Sex					0.79
Women-only trials	3	37	3148	1.29 [0.68, 2.44]
Trials with men and women	6	460	43316	1.18 [0.98, 1.42]
Previous fractures					0.73
Yes	2	89	2745	1.11 [0.73, 1.69]
Other ^c	7	408	43719	1.21 [0.99, 1.47]
Calcium intake, mg/d					0.57
≥ 900	3	149	28333	1.10 [0.80, 1.52]
< 900	6	348	18131	1.23 [0.99, 1.52]
Baseline 25OHD, ng/mL					0.69
≥ 20	4	226	36197	1.24 [0.95, 1.61]
< 20	5	271	10267	1.15 [0.90, 1.46]
Trial Duration					0.41
< 1 Year	1	1	686	0.31 [0.01, 7.72]
≥ 1 Year	8	496	45778	1.19 [1.00, 1.43]
Vertebral Fracture
Research area					0.16
High sunlight exposure	1	63	2258	1.25 [0.76, 2.07]
Low sunlight exposure	3	52	5431	0.73 [0.42, 1.27]
Vitamin D dose and frequency					0.17
≥ 800 IU/d	2	6	2745	1.80 [0.38, 8.51]
< 800 IU/d	0	0	0	NA
Intermittent high-dose (once every year)	1	63	2258	1.25 [0.76, 2.07]
Intermittent high-dose (other frequencies ^b)	1	46	2686	0.64 [0.35, 1.16]
Sex					0.16
Women-only trials	1	63	2258	1.25 [0.76, 2.07]
Trials with men and women	3	52	5431	0.73 [0.42, 1.27]
Previous fractures					0.43
Yes	2	6	2745	1.80 [0.38, 8.51]
Other ^c	2	109	4944	0.94 [0.64, 1.38]
Calcium intake, mg/d					0.16
≥ 900	1	63	2258	1.25 [0.76, 2.07]
< 900	3	52	5431	0.73 [0.42, 1.27]
Baseline 25OHD, ng/mL					NA
≥ 20	0	0	0	NA
< 20	4	115	7689	0.98 [0.68, 1.41]
Trial Duration					NA
< 1 Year	0	/	/	/
≥ 1 Year	4	115	7689	0.98 [0.68, 1.41]
Nonvertebral Fracture
Research area					0.56
High sunlight exposure	5	1817	33970	1.03 [0.94, 1.13]
Low sunlight exposure	3	956	12185	1.08 [0.95, 1.23]
Vitamin D dose and frequency					0.21
≥ 800 IU/d	4	1651	28663	0.99 [0.89, 1.09]
< 800 IU/d	0	0	0	NA
Intermittent high-dose (once every year)	2	810	11698	1.14 [0.99, 1.31]
Intermittent high-dose (other frequencies ^b)	2	312	5794	1.14 [0.90, 1.43]
Sex					0.23
Women-only trials	2	245	2944	1.22 [0.94, 1.59]
Trials with men and women	6	2528	43211	1.03 [0.95, 1.12]
Previous fractures					0.99
Yes	2	371	2745	1.05 [0.84, 1.30]
Other ^c	6	2402	43410	1.05 [0.96, 1.14]
Calcium intake, mg/d					0.3
≥ 900	3	1505	28176	1.01 [0.91, 1.12]
< 900	5	1268	17979	1.09 [0.98, 1.23]
Baseline 25OHD, ng/mL					0.37
≥ 20	5	2177	41152	1.03 [0.94, 1.12]
< 20	3	596	5003	1.12 [0.95, 1.33]
Trial Duration					0.56
< 1 Year	2	21	733	1.04 [0.45, 2.44]
≥ 1 Year	4	1802	33307	1.03 [0.94, 1.13]
Abbreviations: OR, odds ratio; CI, confidence interval; 25OHD, 25-hydroxyvitamin D.
^a P value for differences between subgroups.
^b Other frequencies include once every 3 or 4 months-and once every 1 week or month.
^c Includes previous no fracture, partial fracture, and missing fracture data.

Download PDF

Version 1

posted

You are reading this latest preprint version

Association between vitamin D supplementation and fracture incidence in community-dwelling older adults: an updated systematic review and meta-analysis of randomized controlled trials

Status:

Version 1

Abstract

Figures

Introduction

Methods

Statistical analysis

Results

Discussion

Declarations

Funding:

Acknowledgements:

References

Tables

Supplementary Files

Status:

Version 1