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RCT
ACE Report #5855

Intramedullary nailing of closed tibial fracture: rhBMP2-CPM augmentation not recommended


Study Type:Randomized Trial
OE Level Evidence:2
Journal Level of Evidence:2

Efficacy and Safety of Recombinant Human Bone Morphogenetic Protein-2/Calcium Phosphate Matrix for Closed Tibial Diaphyseal Fracture: A Double-Blind, Randomized, Controlled Phase-II/III Trial

J Bone Joint Surg Am. 2013 Dec 4;95(23):2088-96. doi: 10.2106/JBJS.L.01545

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Synopsis

387 patients with closed tibial fractures were randomized in this study to investigate the efficacy and safety of the local application of recombinant human bone morphogenetic protein 2 (rhBMP-2) within a calcium phosphate matrix (CPM) in the treatment of closed tibial fractures. Participants were subject to intramedullary nail fixation in 1 of 4 treatment protocols: 1) nail fixation alone (standard of care), 2) augmented with 1.0mg/mL rhBMP-2/CPM, 3) augmented with 2.0mg/mL rhBMP-2/CPM, or 4) augmented with buffer/CPM. The study was terminated early due to futility, with a lack of efficacy in time to fracture union.

Publication Funding Details +
Funding:
Industry funded
Sponsor:
Wyeth Research
Conflicts:
Other

Risk of Bias

6.5/10

Reporting Criteria

19/21

Fragility Index

N/A

Was the allocation sequence adequately generated?

Was allocation adequately concealed?

Blinding Treatment Providers: Was knowledge of the allocated interventions adequately prevented?

Blinding Outcome Assessors: Was knowledge of the allocated interventions adequately prevented?

Blinding Patients: Was knowledge of the allocated interventions adequately prevented?

Was loss to follow-up (missing outcome data) infrequent?

Are reports of the study free of suggestion of selective outcome reporting?

Were outcomes objective, patient-important and assessed in a manner to limit bias (ie. duplicate assessors, Independent assessors)?

Was the sample size sufficiently large to assure a balance of prognosis and sufficiently large number of outcome events?

Was investigator expertise/experience with both treatment and control techniques likely the same (ie.were criteria for surgeon participation/expertise provided)?

Yes = 1

Uncertain = 0.5

Not Relevant = 0

No = 0

The Reporting Criteria Assessment evaluates the transparency with which authors report the methodological and trial characteristics of the trial within the publication. The assessment is divided into five categories which are presented below.

3/4

Randomization

4/4

Outcome Measurements

4/4

Inclusion / Exclusion

4/4

Therapy Description

4/5

Statistics

Detsky AS, Naylor CD, O'Rourke K, McGeer AJ, L'Abbé KA. J Clin Epidemiol. 1992;45:255-65

The Fragility Index is a tool that aids in the interpretation of significant findings, providing a measure of strength for a result. The Fragility Index represents the number of consecutive events that need to be added to a dichotomous outcome to make the finding no longer significant. A small number represents a weaker finding and a large number represents a stronger finding.

Why was this study needed now?

The standard of care for the majority of tibial fractures has become intramedullary fixation. Despite this treatment, these fractures may display delayed healing or non-union, requiring secondary intervention. Osteoconductive proteins, such as recombinant human bone morphogenetic proteins (rhBMP), have been researched as a possible adjuvant in acute fracture treatment to improve fracture and wound-healing. A factor that needs to be considered with such intervention is maintaining the osteoconductive product at the fracture site for a sufficient amount of time to stimulate healing. A calcium phosphate matrix (CPM) carrier is a newly developed product that has displayed promising preliminary results for delivery of the rhBMP to the fracture site.

What was the principal research question?

In intramedullary nailing for closed diaphyseal tibial fractures, does adjuvant rhBMP-2/CPM stimulate healing and reduce time-to-healing compared to standard of care (SOC), measured over 52 weeks postoperatively?

Study Characteristics -
Population:
387 patients who sustained an acute, closed, tibial diaphyseal fracture (Orthopaedic Trauma Association classification 42-A, 42-B, or 42-C).
Intervention:
SOC & 1.0 mg/mL rhBMP-2/CPM group: Patients received fracture fixation with a locked intramedullary nail after reaming, augmented with a 5.0mL injection of reconstituted lypholized rhBMP-2 and CPM with a concentration of 1.0 mg/mL. Posteromedial and/or anterolateral portals were used in combination to adequately deliver the rhBMP/CPM paste intraosseously or periosseously along the fracture cortex depending on fracture configuration (Mean age: 38.7 +/- 14.4) (n=122, 99M/23F) SOC & 2.0 mg/mL rhBMP-2/CPM group: Patients received fracture fixation with a locked intramedullary nail after reaming, augmented with a 5.0mL injection of reconstituted lypholized rhBMP-2 and CPM with a concentration of 2.0 mg/mL. Posteromedial and/or anterolateral portals were used in combination to adequately deliver the rhBMP/CPM paste intraosseously or periosseously along the fracture cortex, depending on fracture configuration (Mean age: 38.9 +/- 13.9) (n=125, 93M/32F)
Comparison:
SOC group: Patients received fracture fixation with a locked intramedullary nail after reaming without augmentation with rhBMP-2 (Mean age: 39.6 +/- 14.7) (n=62, 39M/23F) SOC & buffer/CPM group: Patients received fracture fixation with a locked intramedullary nail after reaming, augmented with a 5.0mL injection of buffer and CPM (Mean age: 39.6 +/- 14.7) (n=60, 37M/23F)
Outcomes:
The two primary outcomes were time to radipographic union (defined as the presence of bridging callus and/or elimination of fracture lines visualized on at least 3 of 4 diaphyseal aspects on orthogonal radiographs) and time to return to normal function (defined as return to full weight-bearing without pain and without an assistive device). Delayed union was defined as failure to unite by 26 weeks after injury, and nonunion as no visible signs of healing for a minimum of 3 months, starting 9 months after injury. Safety and feasibility were documented through adverse events, concomitant medication use, vital signs, physical examination of the study limb, radiographs for fracture-related complications, laboratory tests, and BMP-2 antibody testing.
Methods:
RCT, Double-blind, Multi-centre (91 sites), Parallel-dose, Phase II/III trial
Time:
Follow-up was conducted at 2, 4, 8, 12, 16, 20, 26, 39, and 52 weeks

What were the important findings?

  • Based on an interim analysis conducted after the enrollment of 180 patients, the study was terminated early due to futility (lack of efficacy in time to fracture union, p>0.476 between rhBMP-2/CPM 2.0mg/mL group and SOC only group). Of the planned 600 patients, 387 were enrolled and randomized.
  • In total, 57% of patients completed the study. The majority of patients who had discontinued participation in the study did so after fracture union had already been achieved. The main reasons for discontinuation were sponsor (Wyeth) withdrawal (15%), loss to follow-up (13%), and patient request (10%).
  • The median time to fracture union was similar between groups (p>0.05). Times to fracture union were 13.1 weeks in the SOC group, 13.0 weeks in the 1.0mg/mL rhBMP-2/CPM group, 15.9 weeks in the 2.0mg/mL rhBMP-2/CPM group, and 15.4 weeks in the buffer/CPM group.
  • Fracture union was achieved similarly between groups: 91.5% for the SOC group, 88.8% for the 1.0mg/mL rhBMP-2/CPM group, 88.4% for the 2.0mg/mL rhBMP-2/CPM group, and 86.2% the buffer/CPM group. Delayed union and nonunion was similarly low between groups: 3-5% across groups. Hardware failure occurred most frequently in the 2.0mg/mL rhBMP-2/CPM group (14%). The rates in the other 3 groups were 6-7%.
  • Groups achieved pain-free full weight-bearing at similar times. Median times to full weight-bearing were 13.4 weeks in the SOC group, 13.4 weeks in the 1.0mg/mL rhBMP-2/CPM group, 14.3 weeks in the 2.0mg/mL rhBMP-2/CPM group, and 16.4 weeks in the buffer/CPM group.
  • The rate of compartment syndrome was also similarly low across groups (2-3%). The rate of grade-3 or -4 edema was low among all four groups (0-2%).
  • Venous thromboembolic events occurred in 2% of the 1.0mg/mL rhBMP/CPM group, 3% of the 2.0mg/mL rhBMP/CPM group, and 2% of the buffer/CPM group, with none occurring in the SOC group. The difference was not statistically significant and the events were judged not related to rhBMP-2 intervention.
  • Postoperative heterotopic ossification and calcinosis was higher among the injected groups.

What should I remember most?

Augmentation with Recombinant human bone morphogenetic protein 2 (rhBMP-2) within a Calcium Phosphate Matrix carrier in intramedullary nail fixation for closed tibial fractures did not demonstrate any beneficial effect in time to union or time to full weight-bearing when compared to non-augmented fixation. Due to this lack of efficacy, the study was terminated early.

How will this affect the care of my patients?

The use of rhBMP-2 with a calcium phosphate matrix carrier in fixation of closed tibial fractures is not suggested based on the findings of this research. Post hoc review suggested that bioavailability of the test article may have been reduced due to changes in its preparation from the phase I to phase II/III trial. Further study may be warranted for optimizing rhBMP-2 preparations and delivery systems.

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