Preclinical therapies to prevent or treat fracture non-union: A systematic review

Abstract

Background: Non-union affects up to 10% of fractures and is associated with substantial morbidity. There is currently no single effective therapy for the treatment or prevention of non-union. Potential treatments are currently selected for clinical trials based on results from limited animal studies, with no attempt to compare results between therapies to determine which have the greatest potential to treat non-union.

Aim: The aim of this systematic review was to define the range of therapies under investigation at the preclinical stage for the prevention or treatment of fracture non-union. Additionally, through meta-analysis, it aimed to identify the most promising therapies for progression to clinical investigation.

Methods: MEDLINE and Embase were searched from 1St January 2004 to 10th April 2017 for controlled trials evaluating an intervention to prevent or treat fracture non-union. Data regarding the model used, study intervention and outcome measures were extracted, and risk of bias assessed.

Results: Of 5,171 records identified, 197 papers describing 204 therapies were included. Of these, the majority were only evaluated once (179/204, 88%), with chitosan tested most commonly (6/204, 3%). Substantial variation existed in model design, length of survival and duration of treatment, with results poorly reported. These factors, as well as a lack of consistently used objective outcome measures, precluded meta-analysis.

Conclusion: This review highlights the variability and poor methodological reporting of current non-union research. The authors call for a consensus on the standardisation of animal models investigating non-union, and suggest journals apply stringent criteria when considering animal work for publication.

Fig 1. PRISMA flow diagram for study inclusion/exclusion.

Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) flow diagram detailing numbers of studies excluded and reasons at each stage of the review process.

Fig 2. Risk of bias analysis.

Bias assessed as per the Systematic Review Centre for Laboratory Animal Experimentation’s (SYRCLE) tool for all 197 studies included.

Fig 3. Bone formation data for studies looking at interventions of human proteins and hormones or cells and tissues.

Forest plot illustrating mean difference in percentage of bone formation as measured by different histological or radiological measures. Abbreviations: ASCs, adipose tissue stem cells; BMSCs, bone marrow stromal cells; CI, confidence interval; HS, heparan sulphate; LV-Wnt10b, lentivirus vector encoding Wnt10b gene; MSCs, mesenchymal stem cells; OGP, osteogenic growth peptide; PRP, platelet rich plasma; PTH, parathyroid hormone; SDF-1, stromal cell derived factor 1; VEGF, vascular endothelial growth factor; WMD, weighted mean difference.

Fig 4. Bone formation data for studies looking at interventions of vibration and motion, gases, minerals, elements and chemicals, pharmaceuticals, animal derivatives or plant extracts.

Forest plot illustrating mean difference in percentage of bone formation as measured by different histological or radiological measures. Abbreviations: BMSCs, bone marrow stromal cells; CI, confidence interval; PRP, platelet rich plasma; PTH, parathyroid hormone; VACC, vanadium absorbed by Coprinus comatus; WMD, weighted mean difference.

Fig 5. Bone volume data for studies looking at interventions of human proteins and hormones, cells and tissues, minerals, elements and chemicals, pharmaceuticals or animal derivatives.

Forest plot illustrating mean difference in cubic millimetre (mm³) of bone volume as measured by different histological or radiological measures. *Since none of the control groups healed, the increase in bone volume was set as 0 and the standard deviation as 0.0000001 in order to be able to illustrate those results in a forest plot using STATA. Abbreviations: BMP2, bone morphogenetic protein 2; BMSCs, bone marrow stromal cells; CI, confidence interval; HA, hyaluronic acid; IGF-1, insulin growth factor-1; MSCs, mesenchymal stem cells; OPG, osteoprotegerin; PI, proteasome inhibitor; SDF-1, stromal cell derived factor 1; VEGF, vascular endothelial growth factor; wks, weeks; WMD, weighted mean difference.

Fig 6. Bone density data for studies looking at interventions of human proteins and hormones, cells and tissues or plant extracts.

Forest plot illustrating mean difference in milligrams per cubic centimetre (mg/cm³) of bone density as measured by different histological or radiological measures. Abbreviations: CI, confidence interval; GSK3, glycogen synthase kinase 3; WMD, weighted mean difference.

Fig 7. Bar graph demonstrating varied study methodology.

Illustration of study-end point in weeks and outcome measure used by all 197 studies.