Optimal Vitamin D3 Supplementation Strategies for Acute Fracture Healing

Study Overview
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Brief Summary
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The objective is to determine the effect of vitamin D3 supplementation on fracture healing at 3 months.

Detailed Description
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Vitamin D supplements are increasingly being recommended to healthy adult fracture patients without an osteoporotic injury. Although this is a relatively new practice pattern, the basis for this adjunct therapy is grounded in the high hypovitaminosis D prevalence rates (up to 75%) among healthy adult fracture patients, and the strong biologic rationale for the role of vitamin D in fracture healing. Briefly, experimental animal studies have demonstrated that the concentration of vitamin D metabolites is higher at a fracture callus compared to the uninjured contralateral bone, vitamin D supplementation leads to decreased time to union and increased callus vascularity, and increases mechanical bone strength compared to controls. While evidence to confirm that vitamin D supplementation improves fracture healing in clinical studies does not exist, the pre-clinical data are compelling and worthy of further investigation. With modern orthopaedic surgical care, rates of complications following tibia and femoral shaft fractures can be as high as 15%. Complications, including delayed union, nonunion, or infection often require secondary surgical procedures and result in profound personal and societal economic costs. While surgeons continue to seek advances in surgical technique, it is becoming increasingly obvious that innovations in orthopaedic techniques or implants are unlikely to eliminate complications. As a result, considerable attention is currently focused on adjunct biologic therapies, such as vitamin D. A recent survey of 397 orthopaedic surgeons showed that only 26% routinely prescribe vitamin D supplementation to adult fracture patients. Of the 93 surgeons who indicated that they routinely prescribe vitamin D supplementation, 29 different dosing regimens were described ranging from low daily doses of 400 IU to loading doses of 600,000 IU. This suggests a high level of clinical uncertainty surrounding the use and optimal dose of vitamin D supplementation in adult fracture patients. If vitamin D supplementation improves fracture healing outcomes, then there is a large opportunity to increase its use; however, before widespread adoption occurs, research is needed to optimize the dosing strategy, establish the dosing safety in the immobilized fracture healing population, and overcome potential medication adherence issues among the often marginalized patients that suffer trauma. The long-term goal of our research program is to conduct a large phase III RCT to determine which dose of vitamin D3 supplementation optimally improves acute fracture healing outcomes in healthy adult patients (18-50 years). The current proposed phase II exploratory trial will perform important preliminary work to test the central hypothesis that vitamin D3 dose and timing of administration is critical for improving fracture healing at 3 months. This trial will also inform the feasibility of the large phase III RCT.

Official Title
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A Blinded Exploratory Randomized Controlled Trial (RCT) to Determine Optimal Vitamin D3 Supplementation Strategies for Acute Fracture Healing

Conditions
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Fracture

Intervention / Treatment
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* Drug: Vitamin D3
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Adult men or women ages 18-50 years Closed or low grade open (Gustilo type I or II) tibial or femoral shaft fracture Fracture treated with a reamed, locked, intramedullary nail Acute fracture (enrolled within 7 days of injury) Provision of informed consent. Exclusion Criteria: Osteoporosis Stress fractures Elevated serum calcium (>10.5 mg/dL) Atypical femur fractures as defined by American Society for Bone and Mineral Research (ASBMR) criteria Pathological fractures secondary to neoplasm or other bone lesion Patients with known or likely undiagnosed disorders of bone metabolism such as Paget's disease, osteomalacia, osteopetrosis, osteogenesis imperfecta etc. Patients with hyperhomocysteinemia Patients with an allergy to vitamin D or another contraindication to being prescribed vitamin D Patients currently taking an over the counter multivitamin that contains vitamin D and are unable or unwilling to discontinue its use for this study Patients who will likely have problems, in the judgment of the investigators, with maintaining follow-up Pregnancy Patients who are incarcerated Patients who are not expected to survive their injuries Other lower extremity injuries that prevent bilateral full weight-bearing by 6 weeks post-fracture.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: High Loading Dose<br>150,000 IU loading dose vitamin D3 at enrolment and 6 weeks, plus daily dose placebo for 3 months. | Drug: Vitamin D3<br> <br> Other: Placebo<br> <br> |
| Experimental: High Daily Dose<br>Loading dose placebo at enrolment and 6 weeks, plus 4,000 IU vitamin D3 per day for 3 months. | Drug: Vitamin D3<br> <br> Other: Placebo<br> <br> |
| Experimental: Low Daily Dose<br>Loading dose placebo at enrolment and 6 weeks, plus 600 IU vitamin D3 per day for 3 months. | Drug: Vitamin D3<br> <br> Other: Placebo<br> <br> |
| Placebo Comparator: Control Group<br>Loading dose placebo at enrolment and 6 weeks, plus daily dose placebo for 3 months. | Other: Placebo<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Fracture Healing Will be Assessed Clinically Using Function IndeX for Trauma (FIX-IT) | FIX-IT is a standardized measure of weight-bearing and pain in patients with lower extremity fractures, specifically tibia and femur fractures. The FIX-IT score ranges from 0 to 12 points in 2 domains: the ability to bear weight (maximum 6 points) and pain at the fracture site (maximum 6 points) The ability to bear weight is assessed through the single-leg stand and ambulation procedures. Pain is assessed through palpation and stress procedures. The scores in both domains, which are weighted equally, are summed to obtain the final total score; the maximum score of 12 indicates the highest level of function. | 3 months post-injury | 
| Fracture Healing Will be Assessed Radiographically Using Radiographic Union Score for Tibial Fractures (RUST) | Radiographic fracture healing was measured using the Radiographic Union Score for Tibial fractures (RUST), which assesses the presence of bridging callus or a persistent fracture line on each of four cortices. This method evaluates two orthogonal radiographic views; each cortex is attributed points ranging from 1 to 3. A fracture in the immediate postoperative period will receive the minimum score, 4, (1 point for each of the four cortices) and a fully consolidated or healed fracture will be assigned the maximum score, 12 (3 points on each of the four cortices). | 3 months post-injury | 
| Fracture Healing Will be Assessed Biochemically Using Serum Levels of the Bone Turnover Marker (BTM) C-terminal Telopeptide of Type I Collagen (CTX) | The BTM C-terminal telopeptide of type I collagen (CTX). CTX is a marker of bone resorption. Clinically important changes in the CTX markers are unknown; however, in a previous study of tibia fracture healing, Veitch et al observed concentrations of both bone turnover markers approximately 100% greater than baseline values.43 Given the large changes observed in these bone turnover markers, the same criteria will be applied for identifying a potentially clinically beneficial regimen and remain powered to detect a mean difference of 20% (SD 30%). | 3 months post-injury | 
| Fracture Healing Will be Assessed Biochemically Using Serum Levels of the Bone Turnover Marker N-terminal Propeptide of Type I Procollagen (P1NP) | P1NP is a bone-formation marker and prior research has found that it is highest at 12 weeks after fractures of the tibial shaft and proximal femur. | 3 months post-injury | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Serum Level of 25(OH)D | Correlations will be assessed between participants' 25(OH)D levels at enrolment, changes in 25(OH)D levels from enrolment to 3 months, and 25(OH)D levels at 3 months and fracture healing | Up to 3 months post-injury | 
| Number of Participants With Adherence With Vitamin D Supplementation | Will measure adherence with vitamin D supplementation based on participants self report at the 6 week and 3 month visits. | Up to 3 months post-injury | 
| Number of Participants With Adverse Events (AE) | A count of the participants who experienced adverse events will measure participant safety | Up to 12 months post-injury | 
| Serum Levels of Calcium | Will measure participant safety | Up to 3 months post-injury | 
| Serum Levels of Parathyroid Hormone | Helps the body to maintain stable levels of calcium in the blood | Up to 3 months post-injury | 
| Count of Participants Who Completed Blood Measures | Will measure participants adherence to the blood measures of the protocol. | Up to 3 months post-injury | 
| Count of Participants Who Completed Radiographic Imaging Measures | Count of participants who completed radiographic imaging measures to determine participant protocol adherence and assists with identifying healing status | up to 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Tibial Shaft, Tibia, Femoral Shaft, Femur, Vitamin D, Fracture Healing