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FracturePhase 2Vita-ShockNCT02786498

Optimal Vitamin D3 Supplementation Strategies for Acute Fracture Healing

A Phase 2 study testing Vitamin D3 in people with Fracture, run by University of Maryland, Baltimore at 2 sites in 2 countries.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial summary

The objective is to determine the effect of vitamin D3 supplementation on fracture healing at 3 months. Read more about this study

Who is it for?
Ages 18 to 50 years
Conditions the study is for
Fracture
What is being tested?
Vitamin D3
Could I receive a placebo?
Yes, some participants may receive a placebo
How many people
102 participants
Where
2 sitesin 2 countries
Study dates
21 Nov 2016to 1 Dec 2021
Phase
Phase 2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 50 years
  • All sexes
  • No healthy volunteers
  • Adult

Who may be able to join

  • 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.

Who cannot join

  • 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.
Show all 14Show fewer
  • 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.

Trial locations and contacts

2 sites in 2 countries.

2 sites in 2 countries

United States1 site

  • University of Maryland, R Adams Cowley Shock Trauma Center

    Baltimore, Maryland, 21201

Other trials in United States

Canada1 site

  • McMaster University, Center for Evidence-Based Orthopaedics

    Hamilton, Ontario, L8L 8E7

Other trials in Canada

About this study

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

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

Read the 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.

Conditions
Fracture
Being tested
Vitamin D3, Placebo
Keywords
Tibial Shaft, Tibia, Femoral Shaft, Femur, Vitamin D, Fracture Healing
Medical subject headings
Fractures, Bone

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

Study groups in NCT02786498
Study groupRoleWhat they receive
High Loading DoseExperimental150,000 IU loading dose vitamin D3 at enrolment and 6 weeks, plus daily dose placebo for 3 months.
Receives: Drug: Vitamin D3; Other: Placebo
High Daily DoseExperimentalLoading dose placebo at enrolment and 6 weeks, plus 4,000 IU vitamin D3 per day for 3 months.
Receives: Drug: Vitamin D3; Other: Placebo
Low Daily DoseExperimentalLoading dose placebo at enrolment and 6 weeks, plus 600 IU vitamin D3 per day for 3 months.
Receives: Drug: Vitamin D3; Other: Placebo
Control GroupPlacebo comparatorLoading dose placebo at enrolment and 6 weeks, plus daily dose placebo for 3 months.
Receives: Other: Placebo

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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.

    Measured: 3 months post-injury

  2. 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).

    Measured: 3 months post-injury

  3. 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%).

    Measured: 3 months post-injury

  4. 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.

    Measured: 3 months post-injury

Secondary outcomes (7)

  1. 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

    Measured: Up to 3 months post-injury

  2. 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.

    Measured: Up to 3 months post-injury

  3. Number of Participants With Adverse Events (AE)

    A count of the participants who experienced adverse events will measure participant safety

    Measured: Up to 12 months post-injury

  4. Serum Levels of Calcium

    Will measure participant safety

    Measured: Up to 3 months post-injury

  5. Serum Levels of Parathyroid Hormone

    Helps the body to maintain stable levels of calcium in the blood

    Measured: Up to 3 months post-injury

  6. Count of Participants Who Completed Blood Measures

    Will measure participants adherence to the blood measures of the protocol.

    Measured: Up to 3 months post-injury

  7. 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

    Measured: up to 12 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted1 Jun 2016 (estimated)
  2. Study start21 Nov 2016
  3. Primary completionAug 2019
  4. Study completion1 Dec 2021

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Other
Allocation
Randomised
Intervention model
Parallel groups
Masking
Triple blind
Who is masked
Participant, Investigator, Outcomes assessor
Enrolment
102 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02786498
Sponsor's protocol ID
HP-00069705
Acronym
Vita-Shock
Status last verified
Mar 2022
First submitted
11 May 2016
Last updated
31 Mar 2022
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No

Publications

  • Sprague S, Petrisor B, Scott T, Devji T, Phillips M, Spurr H, Bhandari M, Slobogean GP. What Is the Role of Vitamin D Supplementation in Acute Fracture Patients? A Systematic Review and Meta-Analysis of the Prevalence of Hypovitaminosis D and Supplementation Efficacy. J Orthop Trauma. 2016 Feb;30(2):53-63. doi: 10.1097/BOT.0000000000000455.

    PubMed 26429406

  • Omeroglu S, Erdogan D, Omeroglu H. Effects of single high-dose vitamin D3 on fracture healing. An ultrastructural study in healthy guinea pigs. Arch Orthop Trauma Surg. 1997;116(1-2):37-40.

    PubMed 9006763

  • Jingushi S, Iwaki A, Higuchi O, Azuma Y, Ohta T, Shida JI, Izumi T, Ikenoue T, Sugioka Y, Iwamoto Y. Serum 1alpha,25-dihydroxyvitamin D3 accumulates into the fracture callus during rat femoral fracture healing. Endocrinology. 1998 Apr;139(4):1467-73. doi: 10.1210/endo.139.4.5883.

    PubMed 9528922

  • Lidor C, Dekel S, Edelstein S. The metabolism of vitamin D3 during fracture healing in chicks. Endocrinology. 1987 Jan;120(1):389-93. doi: 10.1210/endo-120-1-389.

    PubMed 3023034

  • Lidor C, Dekel S, Hallel T, Edelstein S. Levels of active metabolites of vitamin D3 in the callus of fracture repair in chicks. J Bone Joint Surg Br. 1987 Jan;69(1):132-6. doi: 10.1302/0301-620X.69B1.3029136.

    PubMed 3029136

  • Omeroglu H, Ates Y, Akkus O, Korkusuz F, Bicimoglu A, Akkas N. Biomechanical analysis of the effects of single high-dose vitamin D3 on fracture healing in a healthy rabbit model. Arch Orthop Trauma Surg. 1997;116(5):271-4. doi: 10.1007/BF00390051.

    PubMed 9177802

  • Study to Prospectively Evaluate Reamed Intramedullary Nails in Patients with Tibial Fractures Investigators; Bhandari M, Guyatt G, Tornetta P 3rd, Schemitsch EH, Swiontkowski M, Sanders D, Walter SD. Randomized trial of reamed and unreamed intramedullary nailing of tibial shaft fractures. J Bone Joint Surg Am. 2008 Dec;90(12):2567-78. doi: 10.2106/JBJS.G.01694.

    PubMed 19047701

  • Duan X, Al-Qwbani M, Zeng Y, Zhang W, Xiang Z. Intramedullary nailing for tibial shaft fractures in adults. Cochrane Database Syst Rev. 2012 Jan 18;1(1):CD008241. doi: 10.1002/14651858.CD008241.pub2.

    PubMed 22258982

  • Bhandari M, Guyatt GH, Tong D, Adili A, Shaughnessy SG. Reamed versus nonreamed intramedullary nailing of lower extremity long bone fractures: a systematic overview and meta-analysis. J Orthop Trauma. 2000 Jan;14(1):2-9. doi: 10.1097/00005131-200001000-00002.

    PubMed 10630795

  • Bonafede M, Espindle D, Bower AG. The direct and indirect costs of long bone fractures in a working age US population. J Med Econ. 2013;16(1):169-78. doi: 10.3111/13696998.2012.737391. Epub 2012 Oct 22.

    PubMed 23035626

  • Antonova E, Le TK, Burge R, Mershon J. Tibia shaft fractures: costly burden of nonunions. BMC Musculoskelet Disord. 2013 Jan 26;14:42. doi: 10.1186/1471-2474-14-42.

    PubMed 23351958

  • Kanakaris NK, Giannoudis PV. The health economics of the treatment of long-bone non-unions. Injury. 2007 May;38 Suppl 2:S77-84. doi: 10.1016/s0020-1383(07)80012-x.

    PubMed 17920421

  • Bhandari M, Schemitsch EH. Stimulation of fracture healing: osteobiologics, bone stimulators, and beyond. J Orthop Trauma. 2010 Mar;24 Suppl 1:S1. doi: 10.1097/BOT.0b013e3181d2d683. No abstract available.

    PubMed 20182228

  • Marsell R, Einhorn TA. Emerging bone healing therapies. J Orthop Trauma. 2010 Mar;24 Suppl 1:S4-8. doi: 10.1097/BOT.0b013e3181ca3fab.

    PubMed 20182234

  • Schoelles K, Snyder D, Kaczmarek J, Kuserk E, Erinoff E, Turkelson C, Coates V. The Role of Bone Growth Stimulating Devices and Orthobiologics in Healing Nonunion Fractures [Internet]. Rockville (MD): Agency for Healthcare Research and Quality (US); 2005 Sep 21. Available from http://www.ncbi.nlm.nih.gov/books/NBK285118/

    PubMed 25879121

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Vitamin D3 in people with Fracture, run by University of Maryland, Baltimore at 2 sites in 2 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 5 inclusion and 14 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 31 Mar 2022. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 2 sites in United States, Canada. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 1 Apr 2021). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Fracture Healing Will be Assessed Clinically Using Function IndeX for Trauma (FIX-IT) (time frame: 3 months post-injury). The study lists 4 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02786498, which also lists 18 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 31 Mar 2022.

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