Vitamin D Supplementation and Fractures in Adults: A Systematic Umbrella Review of Meta-Analyses of Controlled Trials

Abstract

Context The growing number of systematic reviews/meta-analyses (SR/MAs) on vitamin D (±calcium) for fracture prevention has led to contradictory guidelines. This umbrella review aims to assess the quality and explore the reasons for discrepancy of SR/MAs of trials on vitamin D supplementation for fracture risk reduction in adults. Evidence Acquisition We searched 4 databases (2010-2020), Epistemonikos, and references of included SR/MAs, and we contacted experts in the field. We used AMSTAR-2 for quality assessment. We compared results and investigated reasons for discordance using matrices and sub-group analyses (PROSPERO registration: CRD42019129540). Evidence Synthesis We included 13 SR/MAs on vitamin D and calcium (Ca/D) and 19 SR/MAs on vitamin D alone, compared to placebo/control. Only 2 from 10 SR/MAs on Ca/D were of moderate quality. Ca/D reduced the risk of hip fractures in 8/12 SR/MAs (relative risk (RR) 0.61-0.84), and any fractures in 7/11 SR/MAs (RR 0.74-0.95). No risk reduction was noted in SR/MAs exclusively evaluating community-dwelling individuals or in those on vitamin D alone compared to placebo/control. Discordance in results between SR/MAs stems from inclusion of different trials, related to search periods and eligibility criteria, and varying methodology (using intention to treat, per-protocol, or complete case analysis from individual trials). Vitamin D alone has no protective effect on fracture risk. Conclusions Ca/D reduces the risk of hip and any fractures, possibly driven by findings from institutionalized subjects. Individual participant data meta-analyses of patients on Ca/D with sufficient follow-up period, and subgroup analyses, would unravel determinants for a beneficial response to supplementation.

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

“…Therefore, separating study populations is needed to determine the exact relationship between vitamin D supplementation and fracture. This view is also re ected 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.…”

“…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 signi cant.…”

Role of vitamin D supplementation in the management of musculoskeletal diseases: update from an European Society of Clinical and Economical Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO) working group

“…Many meta-analyses including various numbers of trials, hence of subjects, were recently published [47,[51][52][53][54][55][56][57][58][59][60][61][62][63][64][65][66] (Table 1). In that of Bolland et al [59], which included 81 studies but with only 6% of vitamin D-deficient subjects at baseline, supplementation of vitamin D alone was not associated with a reduction of the incidence of total and hip fractures as well as of falls.…”

“…In a network meta-analysis which tested the effect of different doses of vitamin D, calcium and their combination in randomized controlled trials lasting more than one year in community-dwelling subjects aged over 50 years, vitamin D, calcium or both were not better than placebo or no treatment for the reduction of the risk of any or hip fractures [60]. Very recently, a systematic umbrella review of meta-analyses of controlled trials showed that the combined supplementation of vitamin D and calcium was associated with a reduction in the risk of hip fracture in two-third of 12 meta-analyses (RR 0.61-0.84) and a reduction in the incidence of any fracture in 7 of 11 meta-analyses (RR 0.74-0.95) with greater effect among institutionalized subjects [65]. It should be noted that the baseline levels of vitamin D available in 5 of these meta-analyses were between 21 and 83 nmol/L and that no fracture risk reduction was observed in meta-analyses exclusively evaluating community-dwelling individuals or in those on vitamin D alone [65].…”

“…Very recently, a systematic umbrella review of meta-analyses of controlled trials showed that the combined supplementation of vitamin D and calcium was associated with a reduction in the risk of hip fracture in two-third of 12 meta-analyses (RR 0.61-0.84) and a reduction in the incidence of any fracture in 7 of 11 meta-analyses (RR 0.74-0.95) with greater effect among institutionalized subjects [65]. It should be noted that the baseline levels of vitamin D available in 5 of these meta-analyses were between 21 and 83 nmol/L and that no fracture risk reduction was observed in meta-analyses exclusively evaluating community-dwelling individuals or in those on vitamin D alone [65]. Finally, the review of Li et al [64] included not only pairwise meta-analysis of 35 trials, but also a Bayesian network meta-analysis.…”