Article - Effect of Vitamin D Supplementation on Acute Fracture Healing: A Phase II Screening Randomized Double-Blind Controlled Trial.

Plain Language Summary

Almost half of all adult patients with fractures are vitamin D deficient. The aim of this double-blind, randomised, placebo-controlled trial was to evaluate the efficacy of different vitamin D regimens on the healing of acute tibia and femur fractures. 102 18-50-year-old patients were enrolled in the study and randomised to receive a) two high doses (150,000 IU) at time of injury and after 6 weeks, b) 4000 IU daily, c) 600 IU daily or d) placebo for 3 months. After 3 months, there were no statistically significant differences between the 3 intervention groups with respect to clinical or radiographic outcomes of fracture healing. The authors report a significantly better clinical, but not radiographic, outcome for 4000 IU per day versus placebo with a p-value of 0.15 (note: generally, to be considered statistically significant, p should be < 0.05). Similar results were observed after 12 months. There was no significant correlation between vitamin D levels and fracture healing. The authors concluded that high dose vitamin D may confer a modest benefit for fracture healing but that this requires confirmation from a larger clinical trial.

Expert Review

Reviewer: Karin Elgar

15th Feb 2024

Conflict of interest

None

Take home message

The evidence base for the use of vitamin D supplements in isolation to support fracture healing is weak.

Evidence category

A: Meta-analyses, position-stands, randomized-controlled trials (RCTs)

Summary review

Introduction

Low levels of vitamin D can have negative effects on bone metabolism and healing of fractures
Almost half of all adult fracture patients are vitamin D deficient
The aim of this study was to evaluate the effectiveness of supplementing vitamin D3 (VD3) to improve tibia and femur fracture healing.

Methods

Four-arm, double-blind, randomised, phase II screening, placebo-controlled trial
102 adult patients (aged 18-50 years) with a non-osteoporotic tibial or femoral shaft fracture were randomised into 1 of 4 treatment groups
Just over half (56%) of participants were vitamin D3 deficient at baseline
Intervention groups: 1) 150,000 IU VD3 loading dose at injury and at 6 weeks (high loading) plus daily placebo; 2) placebo loading doses plus 4000 IU VD3 daily (high dose); 3) placebo loading doses plus 600 IU VD3 daily (low dose); 4) placebo loading dose plus placebo daily
Duration: 3 months intervention, further 9 months follow-up. Vitamin D levels were assessed at 6 weeks and 3 months.

Primary outcome measures at 3 months:

Clinical assessment using the Function IndeX for Trauma (FIX-IT)
Radiographic assessment using the Radiographic Union Score for Tibial fractures (RUST).

Secondary outcomes: as above at 6, 9 and 12 months.

Results at 3 months:

No statistically significant difference between high loading and high dose, high and low dose or low dose and placebo for either clinical or radiological assessment (all p-values ≥0.4)
Post-hoc analysis of any dose vs placebo showed no significant difference with either clinical or radiological assessment (all p-values ≥0.25)
Post-hoc analysis of high dose vs placebo showed no significant difference for radiological assessment (p=0.76) whilst it was reported as statistically significant for clinical assessment with p=0.16, with a benefit of VD3 supplementation.
Similar results were seen at 12 months with reported benefit of high dose VD3 for fracture healing with p=0.18
Vitamin D levels improved in all 3 VD3 groups from baseline to 6 weeks
There was no statistically significant correlation between fracture healing and vitamin D level.

Conclusion

The authors conclude that VD3 supplementation may be of modest benefit for fracture healing, but further, larger trials are needed to confirm this.

Clinical practice applications

When working with clients who present with a fracture, it should be noted that the evidence for benefit of vitamin D supplementation alone for fracture healing is weak.

Considerations for future research

Larger studies to increase the statistical power to detect smaller benefits are required
Larger studies may also identify differences in potential benefits between patient populations with different baseline levels of vitamin D.

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Abstract

Nearly half of adult fracture patients are vitamin D deficient (serum 25-hydroxyvitamin D [25(OH)D] levels <20 ng/mL). Many surgeons advocate prescribing vitamin D supplements to improve fracture healing outcomes; however, data supporting the effectiveness of vitamin D supplements to improve acute fracture healing are lacking. We tested the effectiveness of vitamin D supplementation for improving tibia and femur fracture healing. We conducted a single-center, doubleblinded phase II screening randomized controlled trial with a 12-month follow-up. Patients aged 18-50 years receiving an intramedullary nail for a tibia or femoral shaft fracture were randomized 1:1:1:1 to receive (i) 150,000 IU loading dose vitamin D at injury and 6 weeks ( = 27); (ii) 4000 IU vitamin D daily ( = 24); (iii) 600 IU vitamin D daily ( = 24); or (iv) placebo ( = 27). Primary outcomes were clinical fracture healing (Function IndeX for Trauma [FIX-IT]) and radiographic fracture healing (Radiographic Union Score for Tibial fractures [RUST]) at 3 months. One hundred two patients with a mean age of 29 years (standard deviation 8) were randomized. The majority were male (69%), and 56% were vitamin D deficient at baseline Ninety-nine patients completed the 3-month follow-up. In our prespecified comparisons, no clinically important or statistically significant differences were detected in RUST or FIX-IT scores between groups when measured at 3 months and over 12 months. However, in a post hoc comparison, high doses of vitamin D were associated with improved clinical fracture healing relative to placebo at 3 months (mean difference [MD] 0.90, 80% confidence interval [CI], 0.08 to 1.79; = 0.16) and within 12 months (MD 0.89, 80% CI, 0.05 to 1.74; = 0.18). The study was designed to identify potential evidence to support the effectiveness of vitamin D supplementation in improving acute fracture healing. Vitamin D supplementation, particularly high doses, might modestly improve acute tibia or femoral shaft fracture healing in healthy adults, but confirmatory studies are required. The Vita-Shock trial was awarded the Orthopaedic Trauma Association's (OTA) Bovill Award in 2020. This award is presented annually to the authors of the most outstanding OTA Annual Meeting scientific paper. © 2022 The Authors. published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.