This investigation sought to advance the work published in our prior biomechanical study ( A total of 33 adult humeri were used from a previous study where we quantified bone mineral density of the proximal humerus using radiographs and dual-energy x-ray absorptiometry (DEXA), and regional mean cortical thickness and cortical index using radiographs. The bones were fractured in a simulated backwards fall with the humeral head loaded at 2 mm/second via a frustum angled at 30° from the long axis of the bone. Correlations were assessed with ultimate fracture load and these new parameters: cortical index expressed in areas (“areal cortical index”) of larger regions of the diaphysis; the canal-to-calcar ratio used analogous to its application in proximal femurs; and the recently described medial cortical ratio.Objectives
Materials and Methods
The peri-prosthetic tissue response to wear debris
is complex and influenced by various factors including the size, area
and number of particles. We hypothesised that the ‘biologically
active area’ of all metal wear particles may predict the type of
peri-prosthetic tissue response. Peri-prosthetic tissue was sampled from 21 patients undergoing
revision of a small diameter metal-on-metal (MoM) total hip arthroplasty
(THA) for aseptic loosening. An enzymatic protocol was used for
tissue digestion and scanning electron microscope was used to characterise
particles. Equivalent circle diameters and particle areas were calculated.
Histomorphometric analyses were performed on all tissue specimens.
Aspirates of synovial fluid were collected for analysis of the cytokine
profile analysis, and compared with a control group of patients
undergoing primary THA (n = 11) and revision of a failed ceramic-on-polyethylene
arthroplasty (n = 6). The overall distribution of the size and area of the particles
in both lymphocyte and
non-lymphocyte-dominated responses were similar; however, the subgroup
with lymphocyte-dominated peri-prosthetic tissue responses had a
significantly larger total number of particles. 14 cytokines (interleukin (IL)-1ß, IL-2, IL-4, IL-5, IL-6, IL-10,
IL-13, IL-17, interferon (IFN)-γ, and IFN-gamma-inducible protein
10), chemokines (macrophage inflammatory protein (MIP)-1α and MIP-1ß),
and growth factors (granulocyte macrophage colony stimulating factor
(GM-CSF) and platelet derived growth factor) were detected at significantly higher
levels in patients with metal wear debris compared with the control
group. Significantly higher levels for IL-1ß, IL-5, IL-10 and GM-CSF
were found in the subgroup of tissues from failed MoM THAs with
a lymphocyte-dominated peri-prosthetic response compared with those
without this response. These results suggest that the ‘biologically active area’ predicts
the type of
peri-prosthetic tissue response. The cytokines IL-1ß, IL-5, IL-10,
and GM-CSF are associated with lymphocyte-dominated tissue responses
from failed small-diameter MoM THA. Cite this article:
The most frequent cause of failure after total
hip replacement in all reported arthroplasty registries is peri-prosthetic
osteolysis. Osteolysis is an active biological process initiated
in response to wear debris. The eventual response to this process
is the activation of macrophages and loss of bone. Activation of macrophages initiates a complex biological cascade
resulting in the final common pathway of an increase in osteolytic
activity. The biological initiators, mechanisms for and regulation
of this process are beginning to be understood. This article explores current
concepts in the causes of, and underlying biological mechanism resulting
in peri-prosthetic osteolysis, reviewing the current basic science
and clinical literature surrounding the topic.
Small animal models of fracture repair primarily investigate
indirect fracture healing via external callus formation. We present
the first described rat model of direct fracture healing. A rat tibial osteotomy was created and fixed with compression
plating similar to that used in patients. The procedure was evaluated
in 15 cadaver rats and then Objectives
Methods
For over a decade, bisphosphonate administration
has evolved and become the cornerstone of the prevention and treatment
of fragility fractures. Millions of post-menopausal women have relied
on, and continue to depend on, the long-acting, bone density-maintaining
pharmaceutical drug to prevent low-energy fractures. In return,
we have seen the number of fragility fractures decrease, along with
associated costs and emotional benefits. However, with any drug,
there are often concerns with side effects and complications, and
this unique drug class is seeing one such complication in atypical
subtrochanteric femoral fracture, counterproductive to that which
it was designed to prevent. This has created concern over long-term
bisphosphonate administration and its potential link to these atypical
fractures. There is controversial evidence surrounding such a definitive
link, and no protocol for managing these fractures. This review offers the latest information regarding this rare
but increasingly controversial adverse effect and its potential
connection to one of the most successful forms of treatment that
is available for the management of fragility fractures.
This article presents a unified clinical theory
that links established facts about the physiology of bone and homeostasis,
with those involved in the healing of fractures and the development
of nonunion. The key to this theory is the concept that the tissue
that forms in and around a fracture should be considered a specific
functional entity. This ‘bone-healing unit’ produces a physiological
response to its biological and mechanical environment, which leads
to the normal healing of bone. This tissue responds to mechanical
forces and functions according to Wolff’s law, Perren’s strain theory
and Frost’s concept of the “mechanostat”. In response to the local
mechanical environment, the bone-healing unit normally changes with
time, producing different tissues that can tolerate various levels
of strain. The normal result is the formation of bone that bridges
the fracture – healing by callus. Nonunion occurs when the bone-healing
unit fails either due to mechanical or biological problems or a
combination of both. In clinical practice, the majority of nonunions
are due to mechanical problems with instability, resulting in too
much strain at the fracture site. In most nonunions, there is an
intact bone-healing unit. We suggest that this maintains its biological
potential to heal, but fails to function due to the mechanical conditions.
The theory predicts the healing pattern of multifragmentary fractures
and the observed morphological characteristics of different nonunions.
It suggests that the majority of nonunions will heal if the correct
mechanical environment is produced by surgery, without the need
for biological adjuncts such as autologous bone graft. Cite this article:
Corticosteroids are prescribed for the treatment of many medical conditions and their adverse effects on bone, including steroid-associated osteoporosis and osteonecrosis, are well documented. Core decompression is performed to treat osteonecrosis, but the results are variable. As steroids may affect bone turnover, this study was designed to investigate bone healing within a bone tunnel after core decompression in an experimental model of steroid-associated osteonecrosis. A total of five 28-week-old New Zealand rabbits were used to establish a model of steroid-induced osteonecrosis and another five rabbits served as controls. Two weeks after the induction of osteonecrosis, core decompression was performed by creating a bone tunnel 3 mm in diameter in both distal femora of each rabbit in both the experimental osteonecrosis and control groups. An In the osteonecrosis group all measurements of bone healing and maturation were lower compared with the control group. Impaired osteogenesis and remodelling within the bone tunnel was demonstrated in the steroid-induced osteonecrosis, accompanied by inferior mechanical properties of the bone. We have confirmed impaired bone healing in a model of bone defects in rabbits with pulsed administration of corticosteroids. This finding may be important in the development of strategies for treatment to improve the prognosis of fracture healing or the repair of bone defects in patients receiving steroid treatment.
Recent studies have shown that modulating inflammation-related
lipid signalling after a bone fracture can accelerate healing in
animal models. Specifically, decreasing 5-lipoxygenase (5-LO) activity
during fracture healing increases cyclooxygenase-2 (COX-2) expression
in the fracture callus, accelerates chondrogenesis and decreases
healing time. In this study, we test the hypothesis that 5-LO inhibition
will increase direct osteogenesis. Bilateral, unicortical femoral defects were used in rats to measure
the effects of local 5-LO inhibition on direct osteogenesis. The
defect sites were filled with a polycaprolactone (PCL) scaffold
containing 5-LO inhibitor (A-79175) at three dose levels, scaffold
with drug carrier, or scaffold only. Drug release was assessed Objectives
Methods
This study aims to evaluate if micro-CT can work as a method for the 3D assessment and analysis of cancellous bone by comparing micro-CT with undecalcified histological sections in OVX rats. The mandible and tibia of sham, ovariectomised (OVX) and zoledronate-injected ovariectomised (OVX-ZOL) rats were assessed morphometrically. Specimens were scanned by micro-CT. Undecalcified histological sections were manufactured from the specimen scanned by micro-CT and stained with haematoxylin and eosin. Bivariate linear regressions and one-way analysis of variance were undertaken for statistics using SPSS 16.0.1 software.Objectives
Methods
Effects of insulin-like growth factor 1 (IGF1), fibroblast growth
factor 2 (FGF2) and bone morphogenetic protein 2 (BMP2) on the expression
of genes involved in the proliferation and differentiation of osteoblasts
in culture were analysed. The best sequence of growth factor addition
that induces expansion of cells before their differentiation was
sought. Primary human osteoblasts in Objectives
Methods
Congenital pseudarthrosis of the tibia is an uncommon manifestation of neurofibromatosis type 1 (NF1), but one that remains difficult to treat due to anabolic deficiency and catabolic excess. Bone grafting and more recently recombinant human bone morphogenetic proteins (rhBMPs) have been identified as pro-anabolic stimuli with the potential to improve the outcome after surgery. As an additional pharmaceutical intervention, we describe the combined use of rhBMP-2 and the bisphosphonate zoledronic acid in a mouse model of NF1-deficient fracture repair. Fractures were generated in the distal tibiae of neurofibromatosis type 1-deficient ( When only rhBMP but no zoledronic acid was used to promote repair, 75% of fractures in These data support the concept that preventing bone loss in combination with anabolic stimulation may improve the outcome following surgical treatment for children with congenital pseudarthoris of the tibia and NF1.
There are many guidelines that help direct the management of
patients with metal-on-metal (MOM) hip arthroplasties. We have undertaken
a study to compare the management of patients with MOM hip arthroplasties in
different countries. Six international tertiary referral orthopaedic centres were
invited to participate by organising a multi-disciplinary team (MDT)
meeting, consisting of two or more revision hip arthroplasty surgeons
and a musculoskeletal radiologist. A full clinical dataset including
history, blood tests and imaging for ten patients was sent to each
unit, for discussion and treatment planning. Differences in the
interpretation of findings, management decisions and rationale for
decisions were compared using quantitative and qualitative methods.Aims
Methods
We have evaluated the effect of the short-term administration of low therapeutic doses of modern COX-2 inhibitors on the healing of fractures. A total of 40 adult male New Zealand rabbits were divided into five groups. A mid-diaphyseal osteotomy of the right ulna was performed and either normal saline, prednisolone, indometacin, meloxicam or rofecoxib was administered for five days. Radiological, biomechanical and histomorphometric evaluation was performed at six weeks. In the group in which the highly selective anti-COX-2 agent, rofecoxib, was used the incidence of radiologically-incomplete union was similar to that in the control group. All the biomechanical parameters were statistically significantly lower in both the prednisolone and indometacin (p = 0.01) and in the meloxicam (p = 0.04) groups compared with the control group. Only the fracture load values were found to be statistically significantly lower (p = 0.05) in the rofecoxib group. Histomorphometric parameters were adversely affected in all groups with the specimens of the rofecoxib group showing the least negative effect. Our findings indicated that the short-term administration of low therapeutic doses of a highly selective COX-2 inhibitor had a minor negative effect on bone healing.
The literature on fracture repair has been reviewed. The traditional concepts of delayed and nonunion have been examined in terms of the phased and balanced anabolic and catabolic responses in bone repair. The role of medical manipulation of these inter-related responses in the fracture healing have been considered.
We performed a retrospective review of all patients
admitted to two large University Hospitals in the United Kingdom
over a 24-month period from January 2008 to January 2010 to identify
the incidence of atypical subtrochanteric and femoral shaft fractures
and their relationship to bisphosphonate treatment. Of the 3515 patients
with a fracture of the proximal femur, 156 fractures were in the
subtrochanteric region. There were 251 femoral shaft fractures.
The atypical fracture pattern was seen in 27 patients (7%) with
29 femoral shaft or subtrochanteric fractures. A total of 22 patients
with 24 atypical fractures were receiving bisphosphonate treatment at
the time of fracture. Prodromal pain was present in nine patients
(11 fractures); 11 (50%) of the patients on bisphosphonates suffered
12 spontaneous fractures, and healing of these fractures was delayed
in a number of patients. This large dual-centre review has established
the incidence of atypical femoral fractures at 7% of the study population,
81% of whom had been on bisphosphonate treatment for a mean of 4.6
years (0.04 to 12.1). This study does not advocate any change in the use of bisphosphonates
to prevent fragility fractures but attempts to raise awareness of
this possible problem so symptomatic patients will be appropriately
investigated. However, more work is required to identify the true
extent of this new and possibly increasing problem.
We studied the effects of hyperbaric oxygen (HBO) and zoledronic acid (ZA) on posterior lumbar fusion using a validated animal model. A total of 40 New Zealand white rabbits underwent posterior lumbar fusion at L5–6 with autogenous iliac bone grafting. They were divided randomly into four groups as follows: group 1, control; group 2, HBO (2.4 atm for two hours daily); group 3, local ZA (20 μg of ZA mixed with bone graft); and group 4, combined HBO and local ZA. All the animals were killed six weeks after surgery and the fusion segments were subjected to radiological analysis, manual palpation, biomechanical testing and histological examination. Five rabbits died within two weeks of operation. Thus, 35 rabbits (eight in group 1 and nine in groups 2, 3 and 4) completed the study. The rates of fusion in groups 3 and 4 (p = 0.015) were higher than in group 1 (p <
0.001) in terms of radiological analysis and in group 4 was higher than in group 1 with regard to manual palpation (p = 0.015). We found a statistically significant difference in the biomechanical analysis between groups 1 and 4 (p = 0.024). Histological examination also showed a statistically significant difference between groups 1 and 4 (p = 0.036). Our results suggest that local ZA combined with HBO may improve the success rate in posterior lumbar spinal fusion.
MicroRNAs (miRNAs ) are small non-coding RNAs
that regulate gene expression. We hypothesised that the functions
of certain miRNAs and changes to their patterns of expression may
be crucial in the pathogenesis of nonunion. Healing fractures and
atrophic nonunions produced by periosteal cauterisation were created
in the femora of 94 rats, with 1:1 group allocation. At post-fracture
days three, seven, ten, 14, 21 and 28, miRNAs were extracted from
the newly generated tissue at the fracture site. Microarray and
real-time polymerase chain reaction (PCR) analyses of day 14 samples
revealed that five miRNAs, miR-31a-3p, miR-31a-5p, miR-146a-5p,
miR-146b-5p and miR-223-3p, were highly upregulated in nonunion.
Real-time PCR analysis further revealed that, in nonunion, the expression
levels of all five of these miRNAs peaked on day 14 and declined
thereafter. Our results suggest that miR-31a-3p, miR-31a-5p, miR-146a-5p,
miR-146b-5p and miR-223-3p may play an important role in the development
of nonunion. These findings add to the understanding of the molecular mechanism
for nonunion formation and may lead to the development of novel
therapeutic strategies for its treatment. Cite this article:
This study reports the results of 38 total hip
arthroplasties (THAs) in 33 patients aged <
50 years, using the
JRI Furlong hydroxyapatite ceramic (HAC)-coated femoral component.
This represents an update of previous reports of the same cohort
at ten and 16 years, which were reported in 2004 and 2009, respectively.
We describe the survival, radiological and functional outcomes at
a mean follow-up of 21 years (17 to 25). Of the surviving 34 THAs,
one underwent femoral revision for peri-prosthetic fracture after
21 years, and one patient (one hip) was lost to follow-up. Using
aseptic loosening as the end-point, 12 hips (31.5%) needed acetabular
revision but none needed femoral revision, demonstrating 100% survival
(95% confidence interval 89 to 100). In young patients with high demands, the Furlong HAC–coated femoral
component gives excellent long-term results. Cite this article:
We have examined the deterioration of implant fixation after withdrawal of parathyroid hormone (PTH) in rats. First, the pull-out force for stainless-steel screws in the proximal tibia was measured at different times after withdrawal. The stimulatory effect of PTH on fixation was lost after 16 days. We then studied whether bisphosphonates could block this withdrawal effect. Mechanical and histomorphometric measurements were conducted for five weeks after implantation. Subcutaneous injections were given daily. Specimens treated with either PTH or saline during the first two weeks showed no difference in the mechanical or histological results (pull-out force 76 N