Purpose of the study: The current approach for improving the performance of compact bone substitutes is to seed them with selected mesenchymatous stem cells amplified and differentiated to the osteoblastic line in vitro. We hypothesized that the preservation of all these elements in the bone marrow would be most effective for bone tissue formation. Material and methods: Subcutaneous and intramuscular implantation in C57BL/6 mice. We developed a new approach for bone tissue engineering based on an extemporaneous incorporation of total bone marrow into an injectable bone substitute (IBS2). IBS2 is a new polymerizable hydrogel associated with beads of calcium phosphate (BCP) which can be used to implant total bone marrow. A subcutaneous and intramuscular implantation model in mice was tested to analyze the feasibility of this type of graft. Total bone marrow cells from C57BL/6 male mice were seeded in IBS (10 million cells per 100 microliters). This implant was injected subcutaneously (dorsal position) and intramuscularly (left hind foot) in C57BL/6 female mice. TRAP activity was measured under optical microscopy on paraffin embedded HES stained slices at 4 and 8 weeks. Results and discussion: Incorporation of total bone marrow cells in injectable IBS2 produced implants which were rich in mesenchymatous cells, vessels, osteo-clasts, collagen fibers, and osteoid tissue. This demonstrated the great potential of this new approach. In addition, this method is simple and can be performed in the operative room without ex vivo culture. Comparison of this model of extemporaneous cell therapy with a graft of meschymatous cells amplified ex vivo is currently under way

The purpose of this study is to enhance massive bone allografts osseointegration used to reconstruct large bone defects. These allografts show >50% complication rate requiring surgical revision in 20% cases. A new protocol for total bone decellularisation exploiting the vasculature can offer a reduction of postoperative complication by annihilating immune response and improving cellular colonization/ osseointegration. The nutrient artery of 18 porcine bones - humerus/femur/radius/ulna - was cannulated. The decellularization process involved immersion and sequential perfusion with specific solvents over a course of one week. Perfusion was realized by a peristaltic pump (mean flow rate: 6ml/min). The benefit of arterial perfusion was compared to a control group kept in immersion baths without perfusion. Bone samples were processed for histology (HE, Masson's trichrome and DAPI for cell detection), immunohistochemistry (IHC : Collagen IV/elastin for intraosseous vascular system evaluation, Swine Leukocyte Antigen – SLA for immunogenicity in addition to cellular clearance) and DNA quantification. Sterility and solvent residues in the graft were also evaluated with thioglycolate test and pH test respectively. Compared to native bones, no cells could be detected and residual DNA was <50ng/mg dry weight. Intramedullary spaces were completely cleaned. IHC showed the preservation of intracortical vasculature with channels bounded by Collagen IV and elastin within Haversian systems. IHC also showed a significant decrease in SLA signaling. All grafts were sterile at the last decellularization step and showed no solvent residue. The control group kept in immersion baths, paired with 6 perfused radii/ulnae, showed that the perfusion is mandatory to ensure complete decellularisation. Our results prove the effectiveness of a new concept of total bone decellularisation by perfusion. These promising results could lead to a new technique of Vascularized Composite Allograft transposable to pre-clinical and clinical models

Hip fractures are associated with poor outcomes and high mortality rates of 30%. The current gold standard to measure bone fragility is a Dual-Energy X-ray Absorptiometry (DEXA) scan measuring bone mineral density. Yet DEXA under-diagnoses bone fragility by 50% (1). To combat the burden of bone fragility, this experimental study combined ultrasound (US) with a sophisticated computational algorithm, namely full wave inversion (FWI), to evaluate femoral bone structure. The aims were to assess the association of bone structure between the proximal femoral diaphysis and femoral neck; secondly to evaluate whether transverse ultrasound could assess bone structure of the proximal femoral diaphysis. Bone structure of 19 ex vivo human femora was assessed by micro-CT analysis (mean age 88.11 years, male:female 13:6)(Nikon HMXST 225). Using ImageJ/BoneJ, three 10.2mm subsections of proximal diaphysis and femoral neck underwent analysis: the total bone volume fraction, cortical parameters (bone volume fraction, porosity, thickness) and trabecular parameters (porosity, thickness, spacing and connectivity). A unique US prototype was developed to analyse fifteen femoral diaphyseal subsections using two P4-1 transducers with a novel tomography sequence (Verasonics, Matlab ver R2019a, FWI TRUST protocol). Comparative quantitative analysis of US and Micro-CT measurements was assessed (Graphpad Prism 8.3.1). Micro-CT analysis of the proximal femoral diaphysis demonstrated low correlation to the femoral neck (Pearson r −0.54 to 0.55). US was able to capture cortical structure, though a wide limit of agreement seen when compared to micro-CT analysis (Bland-Altman range 36–59% difference). This novel US technique was able to capture cortical bone structure. Improvements in methodology and technology are required to improve the analysis of trabecular bone and overall accuracy. Further evaluation of US and FWI is required to develop the technique and determine its role in clinical practice

Aims

This meta-analysis and systematic review aimed to comprehensively investigate the effects of vitamin K supplementation on bone mineral density (BMD) at various sites and bone metabolism in middle-aged and older adults.

Aims

Gap junction intercellular communication (GJIC) in osteocytes is impaired by oxidative stress, which is associated with age-related bone loss. Ageing is accompanied by the accumulation of advanced oxidation protein products (AOPPs). However, it is still unknown whether AOPP accumulation is involved in the impairment of osteocytes’ GJIC. This study aims to investigate the effect of AOPP accumulation on osteocytes’ GJIC in aged male mice and its mechanism.

Local and systemic concentrations of cobalt (Co) and chromium (Cr) ions may be elevated in patients with accelerated tribo-corrosion at prosthesis bearing surfaces and modular taper junctions. Previous studies by us and others have shown that exposure to these metals negatively affect the viability and function of osteoblasts and osteoclasts in vitro, with implications for bone health. More recently, we have observed an increase in total bone mineral density and reduced bone turnover (TRAP5b and osteocalcin) in patients with well-functioning metal-on-metal hip resurfacing (MOMHR). Here, we provide data to support the hypothesis that osteoclast differentiation and function is altered in this patient population, and that this effect is transferrable through their serum. Patients with well-functioning MOMHR (n=18) at median follow-up of 8 years were individually matched for gender, age and time-since-surgery to a low-exposure group consisting of patients with metal-on-polyethylene total hip arthroplasty (THA). The median circulating concentrations of Co and Cr for the MOMHR group were 2.53µg/L and 2.5µg/L respectively, compared to 0.02µg/L and 0.03µg/L for the THA group. Monocyte fraction of peripheral blood was isolated from these patients, seeded onto dentine wafers and differentiated into osteoclasts using media supplemented with RANKL and M-CSF (osteoclastogenic media, OM). Cultures were monitored for the onset of resorption, following which they were treated with OM, autologous serum or serum from the other individual within the matched MOMHR - THA pair, all supplemented with RANKL and M-CSF. At the end of the culture, cells were TRAP stained and quantified for total osteoclast number, number of resorbing osteoclasts and percentage resorption using the CellD Software Package (Olympus, Southend-on-Sea, U.K.). For cells differentiated in osteoclastogenic media, the resorbing ability of osteoclasts derived from MOMHR patients was reduced by 30% (P=0.046) compared to THA. Correlation analyses showed that chronic exposure to Co and Cr trends towards negative association with resorption ability of these osteoclasts (r = −0.3, P=0.06). Furthermore, the resorbing ability of osteoclasts generated from MOMHR patients and differentiated in autologous serum was reduced 33% (p < 0 .0001), whilst matched THA serum caused a smaller reduction of 14% (p < 0 .01). When cells derived from THA patients were differentiated in autologous serum, the resorbing ability of osteoclasts was similarly reduced by 35% (p < 0 .0001), whilst the matched MOMHR serum also caused a reduction of 21% (p < 0 .0001). Reduced osteoclastogenic response of precursor cells from patients with higher circulating Co and Cr suggests an inherent change in their potential to differentiate into functional osteoclasts. The data also suggests that functional response of mature osteoclasts generated from patient precursor cells are dependent on the prior systemic metal concentrations and the presence of higher circulating CoCr in patients with MOMHR. These effects are modest, but may explain the subtle increase in systemic bone mineral density and decreased bone turnover observed in patients after 8 years exposure compared to age, sex, and exposure-time matched patients who received a conventional THA

Aims

The distal radius is a major site of osteoporotic bone loss resulting in a high risk of fragility fracture. This study evaluated the capability of a cortical index (CI) at the distal radius to predict the local bone mineral density (BMD).

Aims

Despite the interest in the association of gut microbiota with bone health, limited population-based studies of gut microbiota and bone mineral density (BMD) have been made. Our aim is to explore the possible association between gut microbiota and BMD.

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A growing number of fractures progress to delayed or nonunion, causing significant morbidity and socioeconomic impact. Localized delivery of stem cells and subcutaneous parathyroid hormone (PTH) has been shown individually to accelerate bony regeneration. This study aimed to combine the therapies with the aim of upregulating fracture healing.

Aims

Minimally manipulated cells, such as autologous bone marrow concentrates (BMC), have been investigated in orthopaedics as both a primary therapeutic and augmentation to existing restoration procedures. However, the efficacy of BMC in combination with tissue engineering is still unclear. In this study, we aimed to determine whether the addition of BMC to an osteochondral scaffold is safe and can improve the repair of large osteochondral defects when compared to the scaffold alone.

Aims

The processes linking long-term bisphosphonate treatment to atypical fracture remain elusive. To establish a means of exploring this link, we have examined how long-term bisphosphonate treatment with prior ovariectomy modifies femur fracture behaviour and tibia mass and shape in murine bones.

We have previously observed an increase in total bone mineral density and reduced bone turnover (TRAP5b and osteocalcin) in patients with well-functioning metal-on-metal hip resurfacing (MOMHR). Here, we provide data to support the hypothesis that osteoclast differentiation and function is altered in this patient population, and that this effect is transferrable through their serum. Patients with well-functioning MOMHR (cases, n=18) at a median follow-up of 8 years were individually matched for gender, age and time-since-surgery to a low-exposure group consisting of patients with THA (controls, n=18). The monocyte fraction of patient peripheral blood was isolated and differentiated into osteoclasts on dentine wafers using RANKL and M-CSF supplemented media (osteoclastogenic media, OM). Cultures were monitored for the onset of resorption, at which point the cells were treated with OM, autologous serum or serum from matched MOMHR/THA donors, all supplemented with RANKL and M-CSF. At the end of the culture, cells were TRAP-stained and quantified using CellD Software Package, Olympus. When cells were differentiated in standard osteoclastogenic media, the resorbing ability of osteoclasts derived from MOMHR patients was reduced 22%(p<0.0079) compared to THA. The resorbing ability of osteoclasts generated from MOMHR patients and differentiated in autologous serum was reduced 33%(p<0.0001), whilst matched THA serum caused a smaller reduction of 14%(p<0.01). When cells derived from THA patients were differentiated in autologous serum, the resorbing ability of osteoclasts was similarly reduced by 35%(p<0.0001), whilst the matched MOMHR serum also caused a reduction of 21%(p<0.0001). This data suggests that prior exposure to higher circulating Co and Cr in patients with MOMHR reduces osteoclastogenesis, and that the detrimental effect on the functionality of mature osteoclasts is transferable through the serum. This has implications for systemic bone health of patients with MOMHR or modular taper junctions

A balanced inflammatory response is important for successful fracture healing. The response of osteoporotic fracture healing is deranged and an altered inflammatory response can be one underlying cause. The objectives of this review were to compare the inflammatory responses between normal and osteoporotic fractures and to examine the potential effects on different healing outcomes. A systematic literature search was conducted with relevant keywords in PubMed, Embase, and Web of Science independently. Original preclinical studies and clinical studies involving the investigation of inflammatory response in fracture healing in ovariectomized (OVX) animals or osteoporotic/elderly patients with available full text and written in English were included. In total, 14 articles were selected. Various inflammatory factors were reported; of those tumour necrosis factor-α (TNF-α) and interleukin (IL)-6 are two commonly studied markers. Preclinical studies showed that OVX animals generally demonstrated higher systemic inflammatory response and poorer healing outcomes compared to normal controls (SHAM). However, it is inconclusive if the local inflammatory response is higher or lower in OVX animals. As for clinical studies, they mainly examine the temporal changes of the inflammatory stage or perform comparison between osteoporotic/fragility fracture patients and normal subjects without fracture. Our review of these studies emphasizes the lack of understanding that inflammation plays in the altered fracture healing response of osteoporotic/elderly patients. Taken together, it is clear that additional studies, preclinical and clinical, are required to dissect the regulatory role of inflammatory response in osteoporotic fracture healing.

Cite this article: Bone Joint Res 2020;9(7):368–385.

Purpose: The study was conducted to evaluate the effect of salmon calcitonin (sCT) on fracture healing in normal and hypogonadal male rats. Material and Method: Fifty six male Wistar rats, aged 3 months, were undertaken hemiosteotomy of the distal femur shaft, of standard length and width. Half of the animals had been orchiectomised at the age of 2 months. The animals were divided in 8 groups, 7 rats each, as follow: A, a (normal, no sCT), B, b (normal+Sct), C,c(orchiectomised) and D,d (orchiectomised+Sct). Salmon calcitonin was administered immediately after the hemiosteotomy in a dose of 5IU/day subcutaneously. Groups A, a, C and c were given placebo. The animals of the groups a b, c, and d were killed at 2 weeks, while the animals of the groups A, B, C, and D were killed at 4 weeks. After the euthanasia, total bone density and cortical bone density of the callus was estimated by peripheral quantitative computed tomography (pQCT). Histological and histomorfometric parameters of the callus were estimated as well. Results: The mean cortical bone density was 1221.93±13.82 (g/cm. 3. ±SE) for the group a, 1281.3±13.57 for b, 1221.41±18.24 for c, 1245±17.12 for d, 1173.45±34.14 for A, 1298.9±11 for B, 1280.78±13.68 for C, and 1279.4U19.2 for D. The mean total bone density was 843.95±13.69 (g/cm. 3. ±SE) for the group a, 859.84±26.46 for b, 892.27±25.3 fore, 861.37±10.88 for d, 818.97±32.5 for A, 926.39±19.6 for B, 888.31±24.19 for C, and 912.75±28.13 for D. Values of cortical bone density in group b and B were significantly greater than a and A, respectively (b> a, p=0.01 and B> A, p=0.002). Total bone density of the callus was statistically greater in group B than A (B> A, p=0.01). According to the histological and histomorphometric results, sCT increased the amount of cartilage (p=0.014) and the amount of woven bone (p=0.015) in group b compared to a, while osteoblasts number showed no difference between the two groups. Comparing groups c and d, sCT increased the amount of cartilage (p=0.036) and the amount of woven bone (p=0.0014) in group d compared to c, while decreased osteoblasts number in group d (p=0.03). In four weeks the amount of cartilage is significant greater in group D versus C (p=0.006), as well as the amount of woven bone (p=0.0004). The size of the callus is significant greater in group D compared to C as well (p=0.052). Conclusion: It appears that salmon calcitonin administration improves significantly the parameters of callus bone density in normal rats and increases the amount of cartilaginous callus and woven bone both in normal and orchiectomised rats

Summary Statement. The modulation of both quantity and quality of peri-implant bone with either PTH or loading may be viable options to improve implant fixation and patient outcomes. A strong bone-implant interface is essential for successful joint replacement surgery. This study investigated the differences in bone surrounding and within a porous titanium implant after single or combined treatment with two anabolic bone therapies: intermittent parathyroid hormone (teriparatide) and mechanical loading. Porous titanium implants were inserted bilaterally on the distal lateral femurs of rabbits. The right implant was loaded daily (1 MPa, 50 cycles/day) while the left implant was not. Rabbits received daily PTH injections (20 ug/kg) or saline vehicle. Periprosthetic cancellous bone 0.5, 1.0, and 2.0 mm below the implant surface, bone at the 0.25 mm bone-implant interface and total bone within each implant were examined using tissue-level analyses (quantitative backscattered electron microscopy), cellular analyses (immunohistochemistry staining of osteoblasts with procollagen-1 and TRAP staining of osteoclasts), and shear testing (implant-bone interface). Statistical significance was determined using GEE models (p<0.05). For tissue located 0.5 mm below the implant, significant increases in bone area per total area (BA/TA) were observed with PTH treatment (56%) and with loading (27%). Further, an 18% increase in mineralization density with PTH treatment and a 20% increase in mineralization density with loading was found. Loading effects were not present beyond the 0.5 mm periprosthetic region, but PTH significantly increased BA/TA 2.0 mm below and mineralization density 1.0 mm below the implant. Tissue-level changes were supported by increases in osteoblast activity 0.5 mm below the implant with PTH (79%) and loading (34%), as well as by minimal osteoclast changes. At the 0.25 mm implant-bone interface PTH and loading increased BA/TA (16% and 23%, respectively), but only loading increased mineralization density (7%). Further, total integrated bone area was increased 35% with PTH. Both PTH and loading enhanced the mechanical integrity of the implant-bone; shear strength increased 34% and 60%, respectively. Although combined treatment was not synergistic, both PTH and loading individually enhanced the amount and mineralization density of bone at the implant interface and immediately below the interface, thereby increasing the mechanical strength of the metal-bone interface. This research suggests that modulation of both quantity and quality of peri-implant bone may be viable options to improve implant fixation and patient outcomes

Objective. In this study, we aim to compare total bone amount extracted in total knee arthroplasty in implant design and the bone amount extracted through intercondylar femoral notch cut. Material and Method. In this study, we implemented 10 implants on a total of 50 sawbones from 5 different total knee arthroplasty implant brands namely Nex-Gen Legacy (Zimmer, Warsaw, IN, USA), Genesis 2 PS (Smith&Nephew, Memphis, TN, USA), Vanguard (Biomet Orthopedics Inc., Warsaw, IN, USA), Sigma PS (De Puy, Johnson&Johnson, Warsaw, IN, USA), Scorpio NRG PS (Stryker Co., Kalamazoo, USA). Equal or the closest sizes of each brand on anteroposterior plane were selected, and cuts were made following standard technique(see Fig 1 and 2). Extracted bone pieces were measured in terms of volume and length on three planes, and statistically analysed. The volume of all pieces available after each femoral incision was measured according to Archimedes’ principles. Furthermore, the volume of each intercondylar femoral notch pieces was measured separately from other pieces but with the same method. The measurement of intercondylar femoral notch pieces on 3 planes (medial-lateral, anterior-posterior, superior-inferior) was made using Kanon slide gauge (Ermak Ltd, Istanbul, TR). Femoral notch incision pieces were scanned with CAD/CAM technology using three-dimensional scanner 1 SeriesTM (Dental Wings Inc, Montreal, QC, Canada), and the measurements were confirmed with DWOS CAD 4.0.1 software (Dental Wings Inc, Montreal, QC, Canada)(see figure 3a-e). The volume of 10 intercondylar femoral notch pieces performed through the set of each brand was averaged, and considered as the incision volume of that particular brand. Results. The comparison made by excluding femoral notch cuts did not produce any statistically significant difference between the amounts of bone extracted. The least volumetric value measured in extracted intercondylar femoral notch cut was obtained using Vanguard (3,6±0,4 cm3). The gradually increasing volumes were obtained from Nex-Gen (3,7±0,5 cm3), Sigma (5,7±0,4 cm3), Genesis 2 (6,3±0,3 cm3) and Scorpio NRG (6,7±0,7 cm3), respectively. There was no statistical difference between Genesis 2 and Scorpio NRG, and between Nex-Gen and Vanguard. Conclusion. There are significant differences among implant designs in terms of preserving bone stock, and much of these differences stems from intercondylar femoral notch incision

Bone ingrowth fixation of large diameter, beaded cobalt chromium cups is generally considered to be reliable but this is typically judged radiographically. To date, implant retrieval data of attached bone has been limited. This study evaluated correlations between the pre-revision radiographic appearance and the measured amount of bone attachment on one design of porous coated cup. Methods. Twenty-six monoblock, CoCr Birmingham Hip Resurfacing (BHR, Smith and Nephew, TN, USA) cups with macroscopic beads and hydroxyapatite coating were studied. Seventeen were revised for acetabular malposition with the remainder revised for femoral loosening (4), pain (1), infection (1), dislocation (1) or lysis (2). Median time to revision was 35 months (10 – 70 months). Ten patients were female; the median age of all patients was 54 years. The pre-revision radiographs were visually ranked for cup-bone integration as follows: 0 = none, 1 = < 50%, 2 = 50 – 75%, 3 = 76 – 95%, 4 = > 96% integration. Rankings were made for the superior and inferior aspects, without knowledge of the appearance of bone on the retrievals. The revised cups were photographed at an angle so the dome and the cup periphery were visualized. The area of bone in four equal segments in each of the superior and inferior aspects was measured with image analysis software. A probe was used to differentiate bone from soft tissue. Only bone that covered the beads was counted. Correlation coefficients were calculated for the radiographic and image analysis data. Results. Radiographically, most cups were assessed as having more than 50% of bone attachment and 7 cups were ranked as having almost total integration with bone. Only 2 cups were assessed radiographically as fully loose. Measured total bone attachment ranged from none to 55%. Superior and inferior percent ingrowth were highly correlated (corr=0.68, p<0.001) but there was no correlation between percent bone and x-ray rank (inferior corr=0.01, p=0.96; superior corr=0.23, p=0.26). There was no correlation between cup malpositioning as a reason for revision and x-ray integration ranking (superior p=0.34; inferior p=0.80). Discussion. Despite the radiographic appearance of good fixation, there was little or no correlation between percent area of actual bone attachment and x-ray appearance. One study limitation is the assumption that attached bone was indeed integrated with the beads as destructive sectioning was not done to verify this. Published autopsy retrieval studies have shown that even a small amount of actual ingrowth can provide clinically successful fixation. Another possible limitation was the variable quality of the radiographs. Never-the-less these results raise questions about the accuracy of radiographic analysis of bone fixation. The possibility that inadequate fixation is a cause for pain leading to revision should be considered even when the radiographic appearance indicates otherwise

Introduction: Conservative hip replacements are advantageous because resection of bone in the proximal femur is minimised. This study investigated a new design of conservative hip in the goat model where the femoral head was resected and two hydroxyapatite coated ‘pegs’ were introduced into the femoral neck. The hypothesis was that the ‘pegs’ would provide a direct method of transmitting forces within the femoral neck thus resulting in less adverse bone remodelling and reduced loosening. Bone stock is also preserved should subsequent revision be required. Methods: Eight unilateral implants were inserted into the right femur of adult female goats for 1 year. Retrieved specimens were analysed radiographically and histologically. Image analysis was used to quantify bone attachment and total bone area adjacent to the implant. Tetracycline bone markers quantified bone turnover. Operated hips were compared with non-operated hips. The students t-test was used for comparative statistical analysis where p< 0.05 were classified as significant. Results: Radiographic analysis demonstrated bone loss beneath the cup with increased bone density at the distal end of the pins (fig.1). Light microscopy revealed areas of new and mature bone adjacent to the implant. Osseointegration to the HA coating was observed. Bone markers established significantly decreased bone formation rates (p< 0.05) in bone adjacent to the implant in the operated versus control hips. Image analysis results demonstrated an average bone attachment of 30.94% to the implant surface (fig 2). Greatest bone attachment occurred at the end of the pins (78.99%) contributing 22% of overall attachment to the implant. Least attachment occurred beneath the prosthetic cup (13.82%) and in the medial aspect adjacent to the central pin. Greater total bone area was measured in control hips and no significant correlation between bone attachment to the ‘pegs’ and bone area beneath the prosthetic cup was identified. Discussion: From this study we have concluded that despite the resorption of bone beneath the prosthetic cup, the conservatve hip design investigated remained well fixed in the femur during the 1 year in vivo period. It appears that an implant design that resurfaces the femoral head with two pins used to transmit forces into the femoral neck is a useful approach in conservative hip design

Myostatin (GDF-8) is known to play an important role in muscle regeneration, and myostatin is also expressed during the early phases of fracture healing. In this study we used fluorescent immunohistochemistry to define the temporal and spatial localization of myostatin during muscle and bone repair following deep penetrant injury in a mouse model. We then used hydrogel delivery of exogenous myostatin in the same injury model to determine the effects of myostatin exposure on muscle and bone healing. Results show that while myostatin was constitutively expressed in the cytoplasm of intact skeletal muscle fibers, a pool of intense myostatin staining was observed amongst injured skeletal muscle fibers 12-24 hours post-surgery. Myostatin was also expressed in the soft callus chondrocytes 4 days following osteotomy. Hydrogel delivery of 10 or 100 ug/ml recombinant myostatin decreased fracture callus cartilage area relative to total callus area in a dose-dependent manner by 41% and 80% (p<0.05), respectively, compared to vehicle treatment. Myostatin treatment also dose-dependently decreased fracture callus total bone volume by 23% and 47% (p<0.05), with the higher dose of recombinant myostatin yielding the greatest decrease in callus bone volume. Finally, exogenous myostatin treatment caused a significant, dose-dependent increase in fibrous tissue formation in skeletal muscle. Together, these findings suggest that myostatin may inhibit bone repair after traumatic musculoskeletal injury through both autocrine (soft-callus chondrocytes) and paracrine (surrounding injured muscle fibers) mechanisms. Thus, early pharmacological inhibition of myostatin is likely to improve the regenerative potential of both muscle and bone following deep penetrant musculoskeletal injury

To achieve desirable outcomes in cementless total knee replacement (TKR), sufficient primary stability is essential. The primary stability inhibits excessive motions at the bone-implant interface, hence providing the necessary condition for osseointegration [1]. Primary stability for cementless TKR is provided by press-fit forces between the bone and implant. The press-fit forces depend on several factors including interference fit, friction between bone and implant surface, and the bone material properties. It is expected that bone mineral density (BMD) will affect the stability of cementless TKR [2]. However, the effect of BMD on the primary stability of cementless femoral knee component has not been investigated in vitro. Phantom calibrated CT-scans of 9 distal femora were obtained after the surgical cuts were made by an experienced surgeon. Since the press-fit forces of the femoral component mainly occur in the Anteroposterior (AP) direction, the BMD was measured in the anterior and posterior faces for a depth of 5 mm; this depth was based on stress distributions from a Finite Element Analysis of the same implant design. In addition, four strain gauges were connected to different locations on the implant's outer surface and implant strain measured throughout as an indication of underlying bone strain. A cementless Sigma CR femoral component (DePuy Synthes Joint Reconstruction, Leeds, UK) was then implanted using an MTS machine. In order to simulate a ‘normal’ bone condition, the implanted bone was preconditioned for one hour at a cyclic load of 250–1500 N, and a rate of 1 Hz. Finally, the implants were pushed-off from the bone in a high-flex position. Forces and displacements were recorded both during insertion and push-off tests. Strong correlations were found for insertion and push-off forces with BMD, R. 2. = 0.88 and R. 2. = 0.88, respectively (p < 0.001), so although implantation may be harder in patients with higher BMD, initial stability is also improved. A correlation was also found between final strain and push-off forces (R. 2. = 0.89, p < 0.01) and BMD also showed a strong reverse correlation with total bone relaxation (R. 2. = 0.76, p = 0.023). These results indicate that higher BMD induces higher bone strain, which can lead to improved fixation strength. There is no consensus on the best fixation method for the TKR but some surgeons prefer a cementless design for young and active patients. The results of our study showed that the primary stability of a cementless femoral knee component is directly correlated with the bone mineral density. Therefore, patient selection based on bone quality may increase the likelihood of good osseointegration and adequate long-term fixation for cementless femoral knee components