Optimal Vitamin D3 Supplementation Strategies for Acute Fracture Healing

NCT02786498 | Completed Phase 2 Results DMC FDA Drug

• 1 other identifier: HP-00069705
• Study Type: interventional
• Target: 102
• Locations: 2 countries
• Sites: 2

Brief Summary

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

Conditions

Fracture

Keywords

Tibial Shaft; Tibia; Femoral Shaft; Femur; Vitamin D; Fracture Healing

Outcome Measures

Primary Outcomes (4)

• 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 Outcomes (7)

• Serum Level of 25(OH)D

  Up to 3 months post-injury

• Number of Participants With Adherence With Vitamin D Supplementation

  Up to 3 months post-injury

• Number of Participants With Adverse Events (AE)

  Up to 12 months post-injury

• Serum Levels of Calcium

  Up to 3 months post-injury

• Serum Levels of Parathyroid Hormone

  Up to 3 months post-injury

Study Arms (4)

High Loading Dose

EXPERIMENTAL

150,000 IU loading dose vitamin D3 at enrolment and 6 weeks, plus daily dose placebo for 3 months.

Drug: Vitamin D3; Other: Placebo

High Daily Dose

EXPERIMENTAL

Loading dose placebo at enrolment and 6 weeks, plus 4,000 IU vitamin D3 per day for 3 months.

Drug: Vitamin D3; Other: Placebo

Low Daily Dose

EXPERIMENTAL

Loading dose placebo at enrolment and 6 weeks, plus 600 IU vitamin D3 per day for 3 months.

Drug: Vitamin D3; Other: Placebo

Control Group

PLACEBO COMPARATOR

Loading dose placebo at enrolment and 6 weeks, plus daily dose placebo for 3 months.

Other: Placebo

Interventions

Vitamin D3 DRUG

High Daily Dose; High Loading Dose; Low Daily Dose

Placebo OTHER

Control Group; High Daily Dose; High Loading Dose; Low Daily Dose

Eligibility Criteria

• Age: 18 Years - 50 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• University of Maryland, Baltimore: lead
• McMaster University: collaborator

Study Sites (2)

University of Maryland, R Adams Cowley Shock Trauma Center

Baltimore, Maryland, 21201, United States

Location

McMaster University, Center for Evidence-Based Orthopaedics

Hamilton, Ontario, L8L 8E7, Canada

Location

Related Publications (18)

• 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.

  PMID: 26429406 BACKGROUND

• 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.

  PMID: 9006763 BACKGROUND

• 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.

  PMID: 9528922 BACKGROUND

• 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.

  PMID: 3023034 BACKGROUND

• 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.

  PMID: 3029136 BACKGROUND

• 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.

  PMID: 9177802 BACKGROUND

• 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.

  PMID: 19047701 BACKGROUND

• 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.

  PMID: 22258982 BACKGROUND

• 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.

  PMID: 10630795 BACKGROUND

• 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.

  PMID: 23035626 BACKGROUND

• 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.

  PMID: 23351958 BACKGROUND

• 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.

  PMID: 17920421 BACKGROUND

• 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.

  PMID: 20182228 BACKGROUND

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

  PMID: 20182234 BACKGROUND

• 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/

  PMID: 25879121 BACKGROUND

• 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.

  PMID: 16362144 BACKGROUND

• 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.

  PMID: 31446441 BACKGROUND

• 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.

  PMID: 31768262 DERIVED

MeSH Terms

Conditions

Fractures, Bone

Interventions

Cholecalciferol

Condition Hierarchy (Ancestors)

Wounds and Injuries

Intervention Hierarchy (Ancestors)

Cholestenes; Cholestanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Sterols; Vitamin D; Secosteroids; Membrane Lipids; Lipids

Results Point of Contact

• Title: Dr Gerard Slobogean
• Organization: University of Maryland Baltimore, School of Medicine, Department of Orthopaedics

gslobogean@som.umaryland.edu

410-28-6280

Study Officials

• Gerard Slobogean, MD

  University of Maryland

  PRINCIPAL INVESTIGATOR

• Sheila Sprague, PhD

  McMaster University

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: OTHER
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor of Orthopaedics

Study Record Dates

• First Submitted: May 11, 2016
• First Posted: June 1, 2016
• Study Start: November 21, 2016
• Primary Completion: August 1, 2019
• Study Completion: December 1, 2021
• Last Updated: March 31, 2022
• Results First Posted: April 1, 2021

Record last verified: 2022-03

Locations

CA (1); US (1)