Osteonecrosis of Femoral Head Clinical Trial
Official title:
Transcription Factor Runx2 in Necrotic Femoral Head Tissue: Study Protocol for a Retrospective Non-randomized, Parallel-controlled Clinical Trial
The trial detected mRNA expression of several bone repair-related genes, including Runx2, in the femoral head and neck of patients with osteonecrosis of femoral head (ONFH) . Runx2 expression was compared with that of identical tissue from osteoarthritis patients to identify expression in necrotic femoral head tissue, which will help clarify the role and possible clinical significance of Runx2 in femoral head necrosis, bone repair and reconstruction.
Osteonecrosis of the femoral head (ONFH) is a destructive degenerative disease that can
develop into subchondral and articular facet cartilage collapse. Among proposed pathological
mechanisms underlying ONFH, much attention has been paid to the theory of increased
intraosseous pressure. The core of this theory is an unbalance in osteoblast and adipocyte
differentiation of bone marrow mesenchymal stem cells (BM-MSCs). The occurrence and
development of osteonecrosis has been related to abnormal metabolism and differentiation of
BM-MSCs. Normal adult BM-MSCs can differentiate into adipocytes and osteoblasts to maintain
normal physical status. In response to exogenous stimuli (for example, use of exogenous
hormones or alcohol), the bone marrow microenvironment changes to allow more BM-MSCs to
differentiate into adipocytes, leading to increased bone marrow cavity pressure, thereby
inducing ischemic ONFH.
Overexpression of Runx2, an osteoblast-specific transcription factor, can increase
osteoblast differentiation of BM-MSCs, thereby strengthening the effects of BM-MSC
transplantation to repair bone defects and necrosis. By controlling expression of
osteocalcin, an osteoblast-specific gene, Runx2 also controls osteoblast differentiation and
functioning. Osteocalcin, a common indicator used to evaluate bone formation and conversion
rate, is a bone metabolism-regulating factor generated and secreted by osteoblasts; thus, it
is considered to be a good marker for bone functioning. In a previous study by Chen et al.,
seven patients with glucocorticoid-induced ONFH at Association Research Circulation Osseous
(ARCO) Stage IV were included as an experimental group and seven patients with femoral neck
fracture served as a control group. Immunohistochemical staining and quantitative polymerase
chain reaction (PCR) were used to detect osteocalcin immunoreactivity and Runx2 expression
in femoral head and neck tissue. They found that glucocorticoid-induced ONFH is likely
closely related to osteocalcin.
ONFH results from an interruption of the blood supply to the femoral head or injury-caused
death of chondrocytes and bone marrow components. During subsequent repair processes, bone
morphogenetic proteins (BMPs) not only stimulate BM-MSCs to differentiate into osteoblasts,
but also promote osteoblast growth; BMP-2 is the key factor regulating bone tissue
formation.
Sclerotin loss after ONFH is closely related to an unbalance in osteoclast activity and
differentiation. Osteoprotegerin can inhibit bone absorption of mature osteoblasts and
induce apoptosis of osteoblasts. Osteoprotegerin and its ligand system have been confirmed
as key factors regulating osteoblast formation and differentiation, while bone absorption
plays an important role in the pathogenesis and treatment of osteoporosis, osteoarthritis
and bone tumors.
To the best of our knowledge, there have been no controlled clinical trials examining BMP,
osteocalcin, osteoprotegerin or, in particular, Runx2 messenger RNA (mRNA) expression in
femoral head tissue of patients with ONFH at Ficat Stage III-IV and osteoarthritis. In this
non-randomized, parallel-controlled trial, we will use real-time PCR (RT-PCR) to detect
Runx2, BMP-2, BMP-7 and osteoprotegerin mRNA expression in femoral head tissue from patients
with ONFH at Ficat Stage III-IV. Simultaneously, we will detect osteocalcin immunoreactivity
using an immunohistochemical staining method, and compare with osteoarthritis patients for
the purpose of clarifying mechanisms of these factors in bone reconstruction post-ONFH.
Data collection, management, analysis and open access Data collection: According to the
trial design, a table will be formulated for data collection. Collected data will be input
into an electronic database by professional staff using a double-data entry strategy.
Data management: Information accuracy will be checked when all recruited patients are
followed up. The database will be locked by the researcher in charge and will not be
altered. All information relating to this trial will be preserved by Shengjing Hospital of
China Medical University, China.
Data analysis: The electronic database will be fully disclosed to a professional
statistician for statistical analysis.
Data open access: Published data will be available at www.figshare.com. Statistical analysis
Statistical analysis will be performed by a professional statistician (blinded to grouping)
using SPSS 19.0 software. If Runx2, BMP-2, BMP-7 and osteoprotegerin mRNA expression, as
well as osteocalcin immunoreactivity in the femoral head and neck of patients with ONFH and
osteoarthritis, are normally distributed, a two-sample t-test will be used to compare
differences between groups. If, however, these data are not normally distributed, a
Mann-Whitney U test will be used. A level of P < 0.05 will be considered statistically
significant.
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Observational Model: Case Control, Time Perspective: Prospective
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