Effect of Vitamin D₃ Supplementation on Acute Fracture Healing: A Phase II Screening Randomized Double‐Blind Controlled Trial

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 3 supplements to improve acute fracture healing are lacking. We tested the effectiveness of vitamin D 3 supplementation for improving tibia and femur fracture healing. We conducted a single‐center, double ‐ blinded 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 3 at injury and 6 weeks ( n = 27); (ii) 4000 IU vitamin D 3 daily ( n = 24); (iii) 600 IU vitamin D 3 daily ( n = 24); or (iv) placebo ( n = 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 3 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 3 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; p = 0.16) and within 12 months (MD 0.89, 80% CI, 0.05 to 1.74; p = 0.18). The study was designed to identify potential evidence to support the effectiveness of vitamin D 3 supplementation in improving acute fracture healing. Vitamin D 3 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. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

The Effect of Vitamin D Supplementation for Bone Healing in Fracture Patients: A Systematic Review

“…A final total of 14 studies, assessing a total of 2734 patients, were included to assess fracture outcomes following vitamin D supplementation [ 10 , 14 , 23 – 34 ]. Nine of these were controlled trials of which seven were randomised and two were nonrandomised.…”

“…Five studies were cohort trials of which one was prospective and four were retrospective. One study identified in abstract form during the search was later published in full and also included in the analysis [ 34 ]. Table 1 summarizes the characteristics of the included studies, in order of the outcome investigated, and outlines the main findings.…”

“…There was a wide variation in vitamin D supplementation techniques amongst the studies. The research identified bolus dosing regimens ranging from 100,000 to 300,000 IU [ 14 , 27 , 28 ], daily dosing regimens ranging from 800 to 2000 IU daily [ 23 – 25 , 29 – 31 ], or a combination of bolus and daily dosing [ 26 , 33 , 34 ]. Supplementation forms included oral tablet, liquid drops, or intramuscular injections.…”

“…Eight studies assessed the effect of vitamin D on clinical or radiological union [ 14 , 24 , 27 , 31 – 34 ]. There were two studies which did not distinguish between the union types [ 28 , 32 ].…”

“…There were two studies which did not distinguish between the union types [ 28 , 32 ]. Of the remaining studies, four reported both radiological and clinical outcomes [ 14 , 31 , 33 , 34 ], while two studies reported only radiological outcomes [ 24 , 27 ]. There were five studies which reported no significant difference in complication rates when supplementing fracture patients [ 14 , 24 , 27 , 32 , 34 ].…”