Optimal Vitamin D3 Supplementation Strategies for Acute Fracture Healing
- Registration Number
- NCT02786498
- Lead Sponsor
- University of Maryland, Baltimore
- Brief Summary
The objective is to determine the effect of vitamin D3 supplementation on fracture healing at 3 months.
- Detailed Description
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.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 102
- 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.
- 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.
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Low Daily Dose Placebo Loading dose placebo at enrolment and 6 weeks, plus 600 IU vitamin D3 per day for 3 months. Control Group Placebo Loading dose placebo at enrolment and 6 weeks, plus daily dose placebo for 3 months. High Loading Dose Placebo 150,000 IU loading dose vitamin D3 at enrolment and 6 weeks, plus daily dose placebo for 3 months. High Daily Dose Placebo Loading dose placebo at enrolment and 6 weeks, plus 4,000 IU vitamin D3 per day for 3 months. High Loading Dose Vitamin D3 150,000 IU loading dose vitamin D3 at enrolment and 6 weeks, plus daily dose placebo for 3 months. High Daily Dose Vitamin D3 Loading dose placebo at enrolment and 6 weeks, plus 4,000 IU vitamin D3 per day for 3 months. Low Daily Dose Vitamin D3 Loading dose placebo at enrolment and 6 weeks, plus 600 IU vitamin D3 per day for 3 months.
- Primary Outcome Measures
Name Time Method Fracture Healing Will be Assessed Clinically Using Function IndeX for Trauma (FIX-IT) 3 months post-injury 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.
Fracture Healing Will be Assessed Radiographically Using Radiographic Union Score for Tibial Fractures (RUST) 3 months post-injury 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).
Fracture Healing Will be Assessed Biochemically Using Serum Levels of the Bone Turnover Marker (BTM) C-terminal Telopeptide of Type I Collagen (CTX) 3 months post-injury 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%).
Fracture Healing Will be Assessed Biochemically Using Serum Levels of the Bone Turnover Marker N-terminal Propeptide of Type I Procollagen (P1NP) 3 months post-injury 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.
- Secondary Outcome Measures
Name Time Method Number of Participants With Adverse Events (AE) Up to 12 months post-injury A count of the participants who experienced adverse events will measure participant safety
Serum Level of 25(OH)D Up to 3 months post-injury 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
Count of Participants Who Completed Radiographic Imaging Measures up to 12 months Count of participants who completed radiographic imaging measures to determine participant protocol adherence and assists with identifying healing status
Number of Participants With Adherence With Vitamin D Supplementation Up to 3 months post-injury Will measure adherence with vitamin D supplementation based on participants self report at the 6 week and 3 month visits.
Serum Levels of Parathyroid Hormone Up to 3 months post-injury Helps the body to maintain stable levels of calcium in the blood
Count of Participants Who Completed Blood Measures Up to 3 months post-injury Will measure participants adherence to the blood measures of the protocol.
Serum Levels of Calcium Up to 3 months post-injury Will measure participant safety
Trial Locations
- Locations (2)
University of Maryland, R Adams Cowley Shock Trauma Center
🇺🇸Baltimore, Maryland, United States
McMaster University, Center for Evidence-Based Orthopaedics
🇨🇦Hamilton, Ontario, Canada