Biomarkers of bone healing induced by a regenerative approach based on expanded bone marrow-derived mesenchymal stromal cells

Cytotherapy. 2019 Aug;21(8):870-885. doi: 10.1016/j.jcyt.2019.06.002. Epub 2019 Jul 1.


Background: Safety and feasibility of a regenerative strategy based on the use of culture-expanded mesenchymal stromal cells (MSCs) have been investigated in phase 2 trials for the treatment of nonunion and osteonecrosis of the femoral head (ONFH). As part of the clinical study, we aimed to evaluate if bone turnover markers (BTMs) could be useful for predicting the regenerative ability of the cell therapy product.

Materials and methods: The bone defects of 39 patients (nonunion: n = 26; ONFH: n = 13) were treated with bone marrow-derived MSCs, expanded using a clinical-grade protocol and combined with biphasic calcium phosphate before implantation. Bone formation markers, bone-resorption markers and osteoclast regulatory proteins were measured before treatment (baseline) and after 12 and 24 weeks from surgery. At the same time-points, clinical and radiological controls were performed to evaluate the bone-healing progression.

Results: We found that C-Propeptide of Type I Procollagen (CICP) and C-terminal telopeptide of type-I collagen (CTX) varied significantly, not only over time, but also according to clinical results. In patients with a good outcome, CICP increased and CTX decreased, and this trend was observed in both nonunion and ONFH. Moreover, collagen biomarkers were able to discriminate healed patients from non-responsive patients with a good diagnostic accuracy.

Discussion: CICP and CTX could be valuable biomarkers for monitoring and predicting the regenerative ability of cell products used to stimulate the repair of refractory bone diseases. To be translated in a clinical setting, these results are under validation in a currently ongoing phase 3 clinical trial.

Keywords: bone regeneration; bone turnover marker; mesenchymal stromal cells.

Publication types

  • Clinical Trial, Phase II
  • Controlled Clinical Trial
  • Multicenter Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Biomarkers / blood*
  • Biomarkers / metabolism
  • Bone Marrow Cells
  • Bone Regeneration / physiology*
  • Bone Resorption / metabolism
  • Collagen Type I / blood
  • Collagen Type I / metabolism
  • Female
  • Femur Head Necrosis / metabolism
  • Femur Head Necrosis / pathology
  • Femur Head Necrosis / therapy*
  • Humans
  • Hydroxyapatites / therapeutic use
  • Male
  • Mesenchymal Stem Cell Transplantation / methods*
  • Mesenchymal Stem Cells / cytology
  • Middle Aged
  • Osteoclasts / physiology
  • Peptide Fragments / blood
  • Peptide Fragments / metabolism
  • Peptides / blood
  • Peptides / metabolism
  • Procollagen / blood
  • Procollagen / metabolism


  • Biomarkers
  • Collagen Type I
  • Hydroxyapatites
  • Peptide Fragments
  • Peptides
  • Procollagen
  • collagen type I trimeric cross-linked peptide
  • hydroxyapatite-beta tricalcium phosphate
  • procollagen type I carboxy terminal peptide