Changes in Bone Metabolism Induced by Short-Term Treatment with G-CSF for the Mobilization of Allogeneic Hematopoietic Progenitor Cells.
Authors: Kroschinsky Frank P. , Bergmann Sybille , Poppe-Thiede Kirsten , Siegert Gabriele , Rutt Claudia , Ehninger Gerhard 
Published: April 2020

Short-term treatment with granulocyte colony-stimulating factor (G-CSF) has become a standard procedure for the mobilization of allogeneic peripheral blood progenitor cells (PBPC) in healthy donors. While osteopenia was observed after G-CSF long-term treatment in patients with chronic neutropenia and in G-CSF overexpressing animal models, the information about the effects of G-SCF priming in PBPC donors is limited. Bone pain as the most frequent acute toxicity and the transient increase of serum alkaline phosphatase suggest an effect on bone metabolism also during G-CSF treatment for mobilization. A total of 93 unrelated stem cell donors (21 female, 72 male; median age 35 years) were included in a prospective study to investigate the changes in bone metabolism induced by short-term treatment with G-CSF. Mobilization treatment consisted of 7.5 μg/kg body weight lenograstim (Granocyte™, Chugai Pharma Inc., Tokyo, Japan) for five days. Leukaphereses were performed on day 5 and 6. Samples of blood and urine were taken at pre-donation health-check (before rhG-CSF stimulation, baseline), at the first day of apheresis (leukapheresis) and four weeks after donation (follow-up) and tested for a panel of biochemical markers for bone formation and bone resorption. Stem cell collections were not performed in all donors who were included at baseline, therefore data from leukapheresis are available from 73 donors, and 63 donors were examined at follow-up. Serum bone alkaline phosphatase (BAP) and serum ostase which are both markers for bone formation significantly increased from baseline to leukapheresis (p&lt;0.0001). Both returned to baseline values within 4 weeks after donation. In contrast tartrat-resistent alkaline phosphatase (TRAP) 5b, which is produced by osteoclasts, was found to be decreased at leukapheresis (p=0.001) and at follow-up (p=0.005). The collagen type I crosslinks in urine increased significantly from baseline to follow-up (telopeptides p=0.022; deoxypyridinoline p=0,012). The ligand of receptor activator of NF-kB (RANKL) and osteoprotergerin (OPG), which are members of the TNF receptor family and play a role in the regulation of osteoclast recruitment were also affected by G-CSF treatment, which was reflected by a significant increase of OPG/RANKL-ratio (p=0.01). Serum parathormon (PTH) showed a highly significant increase from baseline to leukapheresis (p&lt;0.0001), but was found at normal ranges in all donors at follow-up. Pearson’s correlation of bone markers with circulating CD34+ hematopoietic progenitors before first leukapheresis did not reveal an impact of these parameters on mobilization efficacy.

In conclusion the results confirm the influence of G-CSF short-term treatment on bone metabolism in allogeneic stem cell donors. An initial osteoblastic stimulation is followed by a period of increased bone resorption which seems to be not finished 4 weeks after G-CSF treatment. However, the changes in urine crosslink concentrations occurred within the normal ranges of the used assays in the vast majority of donors and therefore we do not assume an impact on the safety of the mobilization procedure. The complex regulation of bone metabolism by humoral and cellular effectors and the cause of transient hyperparathyroidism need further investigations.