Clinical trial NCT02786498: Optimal Vitamin D3 Supplementation Strategies for Acute Fracture Healing
Official title: A Blinded Exploratory Randomized Controlled Trial (RCT) to Determine Optimal Vitamin D3 Supplementation Strategies for Acute Fracture Healing
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Fracture
Keywords: Tibial Shaft
Tibia
Femoral Shaft
Femur
Vitamin D
Fracture Healing
Lead sponsor: University of Maryland, Baltimore
Sponsor class: OTHER
Collaborators: name: McMaster University
First posted: 2016-06-01
Enrollment: 102
Sex: ALL
Minimum age (years): 18
Maximum age (years): 50
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: OTHER

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.

Eligibility criteria: Inclusion Criteria:

1. Adult men or women ages 18-50 years
2. Closed or low grade open (Gustilo type I or II) tibial or femoral shaft fracture
3. Fracture treated with a reamed, locked, intramedullary nail
4. Acute fracture (enrolled within 7 days of injury)
5. Provision of informed consent.

Exclusion Criteria:

1. Osteoporosis
2. Stress fractures
3. Elevated serum calcium (\>10.5 mg/dL)
4. Atypical femur fractures as defined by American Society for Bone and Mineral Research (ASBMR) criteria
5. Pathological fractures secondary to neoplasm or other bone lesion
6. Patients with known or likely undiagnosed disorders of bone metabolism such as Paget's disease, osteomalacia, osteopetrosis, osteogenesis imperfecta etc.
7. Patients with hyperhomocysteinemia
8. Patients with an allergy to vitamin D or another contraindication to being prescribed vitamin D
9. Patients currently taking an over the counter multivitamin that contains vitamin D and are unable or unwilling to discontinue its use for this study
10. Patients who will likely have problems, in the judgment of the investigators, with maintaining follow-up
11. Pregnancy
12. Patients who are incarcerated
13. Patients who are not expected to survive their injuries
14. Other lower extremity injuries that prevent bilateral full weight-bearing by 6 weeks post-fracture.

Primary outcomes:
measure: Fracture Healing Will be Assessed Clinically Using Function IndeX for Trauma (FIX-IT)
timeFrame: 3 months post-injury
measure: Fracture Healing Will be Assessed Radiographically Using Radiographic Union Score for Tibial Fractures (RUST)
timeFrame: 3 months post-injury
measure: Fracture Healing Will be Assessed Biochemically Using Serum Levels of the Bone Turnover Marker (BTM) C-terminal Telopeptide of Type I Collagen (CTX)
timeFrame: 3 months post-injury
measure: Fracture Healing Will be Assessed Biochemically Using Serum Levels of the Bone Turnover Marker N-terminal Propeptide of Type I Procollagen (P1NP)
timeFrame: 3 months post-injury
Secondary outcomes:
measure: Serum Level of 25(OH)D
timeFrame: Up to 3 months post-injury
measure: Number of Participants With Adherence With Vitamin D Supplementation
timeFrame: Up to 3 months post-injury
measure: Number of Participants With Adverse Events (AE)
timeFrame: Up to 12 months post-injury
measure: Serum Levels of Calcium
timeFrame: Up to 3 months post-injury
measure: Serum Levels of Parathyroid Hormone
timeFrame: Up to 3 months post-injury
measure: Count of Participants Who Completed Blood Measures
timeFrame: Up to 3 months post-injury
measure: Count of Participants Who Completed Radiographic Imaging Measures
timeFrame: up to 12 months
Other outcomes:
Locations:
city: Baltimore
country: United States
facility: University of Maryland, R Adams Cowley Shock Trauma Center
state: Maryland
city: Hamilton
country: Canada
facility: McMaster University, Center for Evidence-Based Orthopaedics
state: Ontario
Study officials:
affiliation: University of Maryland
name: Gerard Slobogean, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: McMaster University
name: Sheila Sprague, PhD
role: PRINCIPAL_INVESTIGATOR
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