Critical illness-related bone loss is associated with osteoclastic and angiogenic abnormalities

Abstract

Critically ill patients are at increased risk of fractures during rehabilitation, and can experience impaired healing of traumatic and surgical bone fractures. In addition, markers of bone resorption are markedly increased in critically ill patients, while markers of bone formation are decreased. In the current study, we have directly investigated the effect of critical illness on bone metabolism and repair. In a human in vitro model of critical illness, Fluorescence-activated cell sorting (FACS) analysis revealed an increase in circulating CD14þ/CD11bþ osteoclast precursors in critically ill patient peripheral blood compared to healthy controls. In addition, the formation of osteoclasts was increased in patient peripheral blood mononuclear cell (PBMC) cultures compared to healthy controls, both in the presence and absence of osteoclastogenic factors receptor activator of NF-kB ligand (RANKL) and macrophage colony-stimulating factor (M-CSF). Culturing PBMCs with 10% critically ill patient serum further increased osteoclast formation and activity in patient PBMCs only, and neutralization studies revealed that immunoglobulin G (IgG) antibody signaling through the immunoreceptor Fc receptor common g chain III (FcRgIII) played an important role. When analyzing bone formation, no differences in osteogenic differentiation were observed using human periosteal-derived cells (hPDCs) treated with patient serum in vitro, but a decrease in the expression of vascular endothelial growth factor receptor 1 (VEGF-R1) suggested impaired vascularization. This was confirmed using serum-treated hPDCs implanted onto calcium phosphate scaffolds in a murine in vivo model of bone formation, where decreased vascularization and increased osteoclast activity led to a decrease in bone formation in scaffolds with patient serum-treated hPDCs. Together, these findings may help to define novel therapeutic targets to prevent bone loss and optimize fracture healing in critically ill patients. ß

Evaluation of Bone Metabolism in Critically Ill Patients Using CTx and PINP

“…Our findings are also indicative of altered bone turnover in a selected population of critically ill patients which is consistent with current literature showing an association between the duration of critical illness (>5 days) and bone resorption [1, 10]. This BTMs pattern is consistent with previous studies that reported increased bone resorption markers [4, 8–14], increased serum osteoclast precursors [15], increased bone formation, and decreased osteocalcin during critical illness compared with controls [4, 11, 16]. These studies consistently described changes: an increased osteoclastic bone resorption (increased urinary DpD and PyD, serum B-CTX/ICTP), an increase in immature osteoblast number and activity (serum P1CP and PINP), and a reduced activity of mature osteoblasts (serum OC and ALP) [4, 8, 10–17].…”

The association between critical illness and changes in bone turnover in adults: a systematic review

“…A further six studies were identified for full-text review from a manual search of citation lists. Of the 27 fulltext studies reviewed, 16 were excluded for not meeting the predetermined eligibility criteria, resulting in 11 studies included in the final analysis [18][19][20][21][22][23][24][25][26][27][28]. In three of the case-control studies, ICU patients were randomised to an intervention after comparison of baseline data from the ICU cohort was compared to a control cohort [22, 23,26].…”

“…The baseline data from these studies was included in the analysis, whereas the data resulting from the randomised intervention was excluded. One study performed in-vivo analysis of osteoclast number and activity in ICU patients compared to controls, with further in-vitro analysis of osteoclast cells, osteoblastic cells, and serum activation factors [25]. As the in-vitro tests were not recognised tests of bone turnover, they were excluded from the analysis.…”

“…An overview of the included articles (n=11) is presented in Table 3. Four of the studies were cohort study design [18][19][20][21] and the remaining seven were case-control study design [22][23][24][25][26][27][28].…”

Role of myeloid early endothelial progenitor cells in bone formation and osteoclast differentiation in tissue construct based on hydroxyapatite poly(ester‐urethane) scaffolds

“…In addition to this potential influence of EPC on bone formation, the common origin of EPC and osteoclast precursor cells also bears a risk that mononuclear cells (MNC) or EPC transdifferentiate into mature osteoclasts. We used CD11b as a marker for myeloid cells which has been also used to characterize circulating osteoclasts precursors or mature osteoclasts . In accordance with these observations mice suffering from osteopetrosis treated by blood derived mononuclear cells reveal a transient contribution of these cells to the osteoclast populations of treated animals .…”