Optimal Vitamin D3 Supplementation Strategies for Acute Fracture Healing (Vita-Shock)

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.

Study Overview

• Status: Completed
• Conditions: Fracture
• Intervention / Treatment: Other: Placebo; Drug: Vitamin D3

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.

• Study Type: Interventional
• Enrollment (Actual): 102
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • Ontario
    • Hamilton, Ontario, Canada, L8L 8E7
      • McMaster University, Center for Evidence-Based Orthopaedics
• United States
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • University of Maryland, R Adams Cowley Shock Trauma Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 46 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Other
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

4

Arms and Interventions

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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: University of Maryland, Baltimore
• Collaborators: McMaster University
• Investigators: Principal Investigator: Gerard Slobogean, MD, University of Maryland

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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:CD008241. doi: 10.1002/14651858.CD008241.pub2.
• 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.
• 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.
• 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.
• 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. Erratum In: Injury. 2007 Oct;38(10):1224.
• 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.
• Marsell R, Einhorn TA. Emerging bone healing therapies. J Orthop Trauma. 2010 Mar;24 Suppl 1:S4-8. doi: 10.1097/BOT.0b013e3181ca3fab.
• 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/
• Veitch SW, Findlay SC, Hamer AJ, Blumsohn A, Eastell R, Ingle BM. Changes in bone mass and bone turnover following tibial shaft fracture. Osteoporos Int. 2006;17(3):364-72. doi: 10.1007/s00198-005-2025-y. Epub 2005 Dec 15.
• Hojsager FD, Rand MS, Pedersen SB, Nissen N, Jorgensen NR. Fracture-induced changes in biomarkers CTX, PINP, OC, and BAP-a systematic review. Osteoporos Int. 2019 Dec;30(12):2381-2389. doi: 10.1007/s00198-019-05132-1. Epub 2019 Aug 24.
• Sprague S, Bzovsky S, Connelly D, Thabane L, Adachi JD, Slobogean GP; Vita-Shock Investigators. Study protocol: design and rationale for an exploratory phase II randomized controlled trial to determine optimal vitamin D3 supplementation strategies for acute fracture healing. Pilot Feasibility Stud. 2019 Nov 22;5:135. doi: 10.1186/s40814-019-0524-4. eCollection 2019.

Study record dates

Study Major Dates

• Study Start (Actual): November 21, 2016
• Primary Completion (Actual): August 1, 2019
• Study Completion (Actual): December 1, 2021

Study Registration Dates

• First Submitted: May 11, 2016
• First Submitted That Met QC Criteria: May 25, 2016
• First Posted (Estimate): June 1, 2016

Study Record Updates

• Last Update Posted (Actual): March 31, 2022
• Last Update Submitted That Met QC Criteria: March 21, 2022
• Last Verified: March 1, 2022

More Information

Terms related to this study

• Keywords: Vitamin D; Tibia; Fracture Healing; Femur; Tibial Shaft; Femoral Shaft
• Additional Relevant MeSH Terms: Wounds and Injuries; Fractures, Bone; Physiological Effects of Drugs; Micronutrients; Vitamins; Bone Density Conservation Agents; Calcium-Regulating Hormones and Agents; Vitamin D; Cholecalciferol
• Other Study ID Numbers: HP-00069705

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No