Vitamin D Supplementation and Bone Mineral Density: Is There an Effect?
By Traci Pantuso ND, MS
Adjunct Faculty, Bastyr University, Seattle, WA
Dr. Pantuso reports no financial relationships relevant to this field of study.
Synopsis:This systematic review and meta-analysis investigated the effects of vitamin D supplementation on bone mineral density (BMD) and found no significant effect of vitamin D supplementation on the hip or spine and a small and significant increase in femoral neck BMD.
Source:Reid R, et al. Effects of vitamin D supplements on bone mineral density: A systematic review and meta-analysis. Lancet 2014;383:146-155 [Epub 2013 Oct 11].
The authors set out to examine whether vitamin D supplementation without calcium affects bone mineral density (BMD), as the relationship between vitamin D and BMD is not well defined.1 Using the PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) guidelines and a predetermined protocol to perform their review, the authors determined that inclusion criteria were:
- Randomized, controlled trials
- Study populations with an average adult age > 20 years
- Study interventions that only varied in supplementation with vitamin D, and supplementation with vitamin D3 or D2 but not a vitamin D metabolite
- Any other interventions were required to be equally distributed across all groups
- Studies that included BMD data and bone mineral content
- Studies were excluded that had patient populations with disorders that were likely to affect calcium or bone metabolism
The search criteria to identify potential studies was performed using the search engines Web of Science, Embase, and the Cochrane database up to July 8, 2012. The authors used the search terms "vitamin D," "c(h)olecalciferol," or "ergocalciferol," together with either "randomized study" or "randomized trial" or "controlled clinical trial." The reference lists of reviews of vitamin D also were screened for qualifying studies. To perform the statistical analysis, the authors used the percentage of change in BMD as the primary endpoint that was investigated. The authors pooled the data with a random effects meta-analysis model and reported weighted mean differences and 95% confidence intervals (CI). To investigate the effects of vitamin D on BMD, the authors compared the data between the subgroups of trials, which were defined by prespecificed characteristics. The subgroup examples cited in the study were baseline age, vitamin D status, treatment dose, and trial duration. All statistical tests were two-tailed and a P value < 0.05 was considered to be statistically significant. To assess the level of heterogeneity in individual studies, the Cochran's Q statistic and the I2 statistic were calculated with the I2 > 50% used as the threshold for significant heterogeneity. Funnel plots and Egger's regression model were used to assess any publication bias.
They identified 3930 unique publications that were considered for inclusion in the study. Fifty-four articles were retrieved, and 23 met the inclusion criteria and were included in the analysis. In the 23 studies analyzed, 4082 participants (92% women) were included. The mean weighted age for all 23 studies was 59 years old, and in six studies (with a total of 871 participants), the average age was < 50 years. The ethnicity of the participants was predominately white in 19 studies; two studies included were done exclusively in African American individuals, one in a Bangladeshi population, and one in Pakistani immigrants in Denmark. Two of the studies were in overweight populations.
25-hydroxyvitamin D Measurement. In 19 studies, 25-hydroxyvitamin D (25(OH)D) was measured at baseline in all individuals (see Tables 1 and 2). In one study, only 15% of participants had 25(OH)D values; it was not measured in three studies. The mean 25(OH)D was < 30 nmol/L (< 12 ng/mL) in five studies (n = 1181), 30-50 nmol/L (12-20 ng/mL) in three studies (n = 610), 50-75 nmol/L (20-30 ng/mL) in 11 studies (n = 1860), and > 75 nmol/L (30 ng/mL) in one study, the latter in 187 healthy Australian women in early postmenopause (see Tables 1 and 2). The unweighted mean vitamin D ranged from 53 nmol/L to 92 nmol/L, and no CI was reported.
Table 1. Vitamin D Conversion Table between ng/mL to nmol/L
Table 2. Baseline Mean 25(OH)D Measurement
Trial Characteristics. A number of different dosing regimens, including daily, weekly, and monthly oral and annual intramuscular injections, were noted in the individual studies and assessed. Daily average dosing was ≤ 500 IU in six studies (n = 1648), 500-799 IU in four studies (n = 646), and ≥ 800 IU in 13 studies (n = 1788) (see Table 3).2 The trial durations were also variable and ranged from 6 months to 5 years. The weighted mean trial duration was 23.5 months. In 12 studies, calcium was given to all trial groups. In two studies (n = 243), the participants had average total calcium intakes of < 750 mg per day. One study used a crossover design, whereas all others were parallel group study.
Table 3. Type of Vitamin D Supplementation
BMD. BMD was measured between one to five sites (lumbar spine, femoral neck, total hip, trochanter, total body, or forearm) in the included studies. The hip was assessed in 12 studies and the trochanter in three studies. The authors combined the hip and trochanter data in the meta-analysis. No significant effect of vitamin D on BMD was found in the spine, combined hip analyses, total body, or forearm.
Six studies showed beneficial effects on BMD in this meta-analysis from five primary studies out of the 23 total studies (see Table 4).3-7 Four of the five studies reported positive effects at one site only and one study reported beneficial effects in both femoral regions (see Table 4).
Table 4. Characteristics of Positive Studies
Of the five studies with positive outcomes, three reported baseline 25(OH)D levels between 26-36 nmol/L. In the other two positive studies, 25 (OH)D levels in the control groups were 66 and 71 nmol/L (see Table 4). The authors also note that the five positive studies had varying treatment times from 12 months to 24 months. These findings suggest that the baseline 25(OH)D levels and the treatment duration were not factors in the positive outcomes.
All of the positive studies were in women; four were in older white women and one was in Bangladeshi women. The author's state, "that there was no suggestion of ethnic differences in response demonstrated."
Overall Results. No significant effect of vitamin D supplementation on BMD in the hip or spine was demonstrated.
A small and significant increase (0.8 % in femoral neck BMD; 95% CI, 0.2-1.4; P = 0.005) in femoral neck BMD with vitamin D supplementation was demonstrated. However, the authors state "Such a localized effect could be artifactual or could be a chance finding" and that there was evidence of heterogeneity in the studies (I2 = 67%, P = 0.00027).
No significant interactions were found with age, number of participants, sex, study duration, 25(OH)D concentration, vitamin D dose, baseline BMD, or type of DXA machine with meta-regression analysis on the femoral neck BMD effect.
Two studies reported a decreased total-body BMD (P ≤ 0.05) with vitamin D supplementation. The results of the meta-analysis on the eight studies with the total body BMD data did not show a significant effect of vitamin D supplementation on total body BMD in either direction.
The question of whether vitamin D affects BMD is an important question that is applicable to clinicians and patients. The conclusion of this meta-analysis is somewhat surprising, as the investigating authors suggest that vitamin D supplementation to prevent osteoporosis in healthy community-dwelling adults is not indicated. This conclusion is in opposition to recent research studies and the U.S. Institute of Medicine (IOM) recommendation that elderly adults should have an intake of 1200 mg of calcium and 800 IU of vitamin D per day for skeletal health.8-10
Although the conclusion is surprising, the authors' search survey appears to be quite exhaustive. The authors performed the meta-analysis with PRISM guidelines and predetermined protocols. Altogether, the study methodology and results appear to be sound. However, the question of whether vitamin D supplementation affecting BMD is best addressed by a meta-analysis study design is an important one. The benefits of a meta-analysis are the increased statistical power of the study and the increased number of participants; however, there are a number of drawbacks. The effects that vitamin D has on the body and, specifically BMD, are seemingly more complicated than previously understood.
The vitamin D dosing among the included studies was quite variable as was the duration of the trials. In addition, the interaction with calcium supplementation would be incompletely addressed in a format focused on vitamin D supplementation alone. As more information is being ascertained regarding the complexities of the vitamin D pathway, there are many known and unknown factors, such as genetic variation, that were not factored into the individual studies of the meta-analysis and their effects cannot be measured.
The IOM recommendation that elderly adults should have an intake of 1200 mg of calcium and 800 IU of vitamin D per day for skeletal health is further corroborated by other research studies that have larger numbers of participants than the Reid et al study.8-10 Two other studies that have further supported the IOM recommendation are the vitamin D individual Patient Analysis of Randomized Trials (DIPART) group and the Bischoff-Ferrari and colleagues study.8-10
Abrahamsen and colleagues of the DIPART group concluded that vitamin D supplementation of 10-20 mcg without calcium is not effective in preventing fractures. However, Abrahamsen et al concluded that "calcium and vitamin D given together reduce hip fractures and total fractures, and probably vertebral fractures, irrespective of age, sex, or previous fractures" in the DIPART study, which included 68,500 patients from trials in the United States and Europe.9
Bischoff-Ferrari and colleagues also concluded that "high-dose vitamin D supplementation (≥ 800 IU per day) may reduce the risk of hip fracture in persons 65 years of age or older, independently of type of dwelling, age, and sex."10 The Bischoff-Ferrari study included 31,022 patients from 11 double-blind RCTs and also concluded that a 25(OH)D level > 60 nmol/L is optimal to prevent fractures.10
Until the complexities of the vitamin D pathway are further studied and the exact mechanisms of actions of its role in bone mineralization are elucidated, the IOM recommendation of 1200 mg of calcium and 800 IU of vitamin D per day for skeletal health is well substantiated and an effective approach to prevent hip fractures.8-11
- Reid R, et al. Effects of vitamin D supplements on bone mineral density: A systematic review and meta-analysis. Lancet 2014;383:146-155 [Epub 2013 Oct 11].
- Venkatachalam S, et al. A randomized controlled trial of parenteral vitamin D in coeliac disease-bone density changes. Osteoporos Int 2003;14(suppl 4):39-40.
- Dawson-Hughes B, et al. Effect of vitamin D supplementation on wintertime and overall bone loss in healthy postmenopausal women. Ann Intern Med 1991;115:505-512.
- Dawson-Hughes B, et al. Rates of bone loss in postmenopausal women randomly assigned to one of two dosages of vitamin D. Am J Clin Nutr 1995;61:1140-1145.
- Ooms ME, et al. Prevention of bone loss by vitamin D supplementation in elderly women: A randomized double-blind trial. J Clin Endocrinol Metab 1995;80:1052-1058.
- Islam MZ, et al. Effect of vitamin D, calcium and multiple micronutrient supplementation on vitamin D and bone status in Bangladeshi premenopausal garment factory workers with hypovitaminosis D: A double-blinded, randomized, placebo-controlled 1-year intervention. Br J Nutr 2010;104:241-247.
- Harwood RH, et al. A randomized, controlled comparison of different calcium and vitamin D supplementation regimens in elderly women after hip fracture: The Nottingham Neck of Femur (NoNOF) Study. Age Ageing 2004;33:45-51.
- Institute of Medicine, Committee to Review Dietary Reference Intakes for Vitamin D and Calcium. Dietary reference intakes for calcium and vitamin D. Washington, DC: National Academies Press, 2011.
- Abrahamsen B, et al. Patient level pooled analysis of 68,500 patients from seven major vitamin D fracture trials in US and Europe. BMJ 2010;340:B5463.
- Bischoff-Ferrari HA, et al. A pooled analysis of vitamin D dose requirements for fracture prevention. N Engl J Med 2012;367:40-49.
- Rosen CJ. Vitamin-D supplementation: Bones of contention. Lancet 2014;383:108-109.