Bone age is a radiographical assessment used in pediatric medicine due to its relative objectivity in determining biological maturity compared to chronological age and size.1 Currently, Greulich and Pyle (GP) is one of the most common methods used to determine bone age from hand radiographs.2–4 In recent years, new methods were developed to increase the efficiency in bone age analysis like the shorthand bone age (SBA) and the automated artificial intelligence algorithms. The purpose of this study is to evaluate the accuracy and reliability of these two methods and examine if the reduction in analysis time compromises their accuracy. Two hundred thirteen males and 213 females were selected. Each participant had their bone age determined by two separate raters using the GP (M1) and SBA methods (M2). Three weeks later, the two raters repeated the analysis of the radiographs. The raters timed themselves using an online stopwatch while analyzing the radiograph on a computer screen. De-identified radiographs were securely uploaded to an automated algorithm developed by a group of radiologists in Toronto. The gold standard was determined to be the radiology report attached to each radiograph, written by experienced radiologists using GP (M1). For intra-rater variability, intraclass correlation analysis between trial 1 (T1) and trial 2 (T2) for each rater and method was performed. For inter-rater variability, intraclass correlation was performed between rater 1 (R1) and rater 2 (R2) for each method and trial. Intraclass correlation between each method and the gold standard fell within the 0.8–0.9 range, highlighting significant agreement. Most of the comparisons showed a statistically significant difference between the two new methods and the gold standard; however it may not be clinically significant as it ranges between 0.25–0.5 years. A bone age is considered clinically abnormal if it falls outside 2 standard deviations of the chronological age; standard deviations are calculated and provided in GP atlas.6–8 For a 10-year old female, 2 standard deviations constitute 21.6 months which far outweighs the difference reported here between SBA, automated algorithm and the gold standard. The median time for completion using the GP method was 21.83 seconds for rater 1 and 9.30 seconds for rater 2. In comparison, SBA required a median time of 7 seconds for rater 1 and 5 seconds for rater 2. The automated method had no time restraint as bone age was determined immediately upon radiograph upload. The correlation between the two trials in each method and rater (i.e. R1M1T1 vs R1M1T2) was excellent (κ= 0.9–1) confirming the reliability of the two new methods. Similarly, the correlation between the two raters in each method and trial (i.e. R1M1T1 vs R2M1T1) fell within the 0.9–1 range. This indicates a limited variability between raters who may use these two methods. The shorthand bone age method and an artificial intelligence automated algorithm produced values that are in agreement with the gold standard Greulich and Pyle, while reducing analysis time and maintaining a high inter-rater and intra-rater reliability

Purpose of the study: Determining bone age at the wrist is not an easy task and can be a source of error. We elaborated a method for determining bone age at the elbow using an analysis of bone maturation at this localization. Material and methods: The method finetunes the Sauvegrain method and is based on more than ten years of data for the analysis of more than 3600 x-rays. Bone maturation evolves from 0% at birth to 100% marking the end of growth. We propose a digital system for drawing the growth curve from 50% to 100% bone maturation as a function of chronological age. This curve gives the distribution of bone age around the median for each gender. Fifty percent maturation corresponds to onset of adolescence and can be used to define onset of puberty before any other clinical sign; 100% bone maturation corresponds to maximal growth or stature. Specific bone landmarks are used and the method for calculating bone age is presented. Results: It is interesting that a shift of one year or more between bone age calculated at the elbow and that calculated from the wrist. This observation was frequent and suggests that bone age determined at the elbow gives a better reflection of limb maturation. In addition, regular use of this method in daily practice confirmed its usefulness, reliability, and inter- and intra-observer reproducibility. Conclusion: This is a reliable simple method for determining bone maturation. It is easier to use than the wrist method and probably better reflects bone maturation of the limbs

Introduction: Prophylactic pinning of an asymptomatic hip in SCFE is controversial. Bone age has been used as evidence of future contralateral slip risk and used as an indication for such intervention. The efficacy of bone age assessment at predicting contralateral slip was tested in this study. Patients and Methods: 18 Caucasian children prospectively had bone age assessment using wrist and hand x-rays when presenting with a unilateral SCFE. Patients and parents were informed about the chance of con-tralateral slip and risks of prophylactic fixation, and advised to attend hospital immediately on development of symptoms in contralateral hip. After in-situ fixation of the affected side prospective monitoring in outpatient department was performed. Surgical intervention was undertaken if the contralateral hip was symptomatic. Results: Three children (2 boys) went on to develop to a contralateral slip at a mean of 20 months from initial presentation. 6 children (5 boys) were deemed at risk of contralateral slip due to a bone age below 12.5 years for boys and 10.5 for girls. Only one from this group developed a contralateral slip. The relative risk of proceeding to contralateral slip when the bone age is below the designated values was 1 (95% confidence interval of 0.1118 to 8.95). The sensitivity and specificity were 33% and 66% respectively. With positive predictive value of 15% and diagnostic efficiency of 61%. Conclusion: Delayed bone age by itself is not a good predictor of future contralateral slip at initial presentation. Routine prophylactic pinning is not justified based on bone age alone, with the risks of surgical fixation it carries. Prospective long term longitudinal study is required

Introduction: Prophylactic pinning of an asymptomatic hip in SCFE is controversial. Bone age has been used as evidence of future contralateral slip risk and used as an indication for such intervention. The efficacy of bone age assessment at predicting contralateral slip was tested in this study. Patients and Methods: 18 Caucasian children prospectively had bone age assessment using wrist and hand x-rays when presenting with a unilateral SCFE. Patients and parents were informed about the chance of contralateral slip and risks of prophylactic fixation, and advised to attend hospital immediately on development of symptoms in contralateral hip. After in-situ fixation of the affected side prospective monitoring in outpatient department was performed. Surgical intervention was undertaken if the contralateral hip was symptomatic. Results: Three children (2 boys) went on to develop to a contralateral slip at a mean of 20 months from initial presentation. 6 children (5 boys) were deemed at risk of contralateral slip due to a bone age below 12.5 years for boys and 10.5 for girls. Only one from this group developed a contralateral slip. The relative risk of proceeding to contralateral slip when the bone age is below the designated values was 1 (95% confidence interval of 0.1118 to 8.95). Conclusion: Delayed bone age by itself is not a good predictor of future contralateral slip at initial presentation. Routine prophylactic pinning is not justified based on bone age alone, with the risks of surgical fixation it carries. Prospective long term longitudinal study is required

Introduction: Prophylactic pinning of an asymptomatic hip in SCFE is controversial. Bone age has been used as evidence of future contralateral slip risk and used as an indication for such intervention. The efficacy of bone age assessment at predicting contralateral slip was tested in this study. Patients and Methods: 18 Caucasian children prospectively had bone age assessment using wrist and hand x-rays when presenting with a unilateral SCFE. Patients and parents were informed about the chance of con-tralateral slip and risks of prophylactic fixation, and advised to attend hospital immediately on development of symptoms in contralateral hip. After in-situ fixation of the affected side prospective monitoring in outpatient department was performed. Surgical intervention was undertaken if the contralateral hip was symptomatic. Results: Three children (2 boys) went on to develop to a contralateral slip at a mean of 20 months from initial presentation. 6 children (5 boys) were deemed at risk of contralateral slip due to a bone age below 12.5 years for boys and 10.5 for girls. Only one from this group developed a contralateral slip. The relative risk of proceeding to contralateral slip when the bone age is below the designated values was 1 (95% confidence interval of 0.1118 to 8.95). The sensitivity and specificity were 33% and 66% respectively. With positive predictive value of 15% and diagnostic efficiency of 61%. Conclusion: Delayed bone age by itself is not a good predictor of future contralateral slip at initial presentation. Routine prophylactic pinning is not justified based on bone age alone, with the risks of surgical fixation it carries. Prospective long term longitudinal study is required

A chance observation of asymmetrical bone ages in a child with spastic hemiplegia stimulated a prospective gathering of bilateral hand radiographs in 33 hemiplegic patients, and on a single occasion in a control group of 23 patients with leg length discrepancy in the absence of neurological disorder. The bone age assessments according to Greulich and Pyle, which by convention has used the left hand only, were done by a single expert observer blinded to the clinical details. 13 hemiplegic patients (39%) had delayed bone ages of 6 months or more. When present it was always delayed on the hemiplegic side. The mean delay for the whole group was 2.5 months, whereas there was no mean difference in the control group (p = 0.001). The oldest bone age with asymmetry was 14.5 years in males and 12 years in females, indicating that when present the delay “catches up” in the last 2-3 years of growth. In hemiplegia the percentage leg length discrepancy also tends to decrease during later growth, and after 80% of growth the hemiplegic side outgrows the normal leg by a mean of 0.3cm/year. No correlation could be found between the delay of bone age and the severity of either the neurological abnormality or the actual discrepancy of length. The implications for clinical management will be discussed

Osteoarthritis (OA) is mainly caused by ageing, strain, trauma, and congenital joint abnormalities, resulting in articular cartilage degeneration. During the pathogenesis of OA, the changes in subchondral bone (SB) are not only secondary manifestations of OA, but also an active part of the disease, and are closely associated with the severity of OA. In different stages of OA, there were microstructural changes in SB. Osteocytes, osteoblasts, and osteoclasts in SB are important in the pathogenesis of OA. The signal transduction mechanism in SB is necessary to maintain the balance of a stable phenotype, extracellular matrix (ECM) synthesis, and bone remodelling between articular cartilage and SB. An imbalance in signal transduction can lead to reduced cartilage quality and SB thickening, which leads to the progression of OA. By understanding changes in SB in OA, researchers are exploring drugs that can regulate these changes, which will help to provide new ideas for the treatment of OA. Cite this article: Bone Joint Res 2023;12(9):536–545

Cemented femoral stems with force closed fixation designs have shown good clinical results despite high early subsidence. A new triple-tapered stem in this category (C-stem AMT) was introduced in 2005. This study compares this new stem with an established stem of similar design (Exeter) in terms of migration (as measured using radiostereometric analysis), peri-prosthetic bone remodelling (measured using dual energy x-ray densitometry, DXA), Oxford Hip Score, and plain radiographs. . A total of 70 patients (70 hips) with a mean age of 66 years (53 to 78) were followed for two years. Owing to missing data of miscellaneous reasons, the final analysis represents data from 51 (RSA) and 65 (DXA) patients. Both stems showed a typical pattern of migration: Subsidence and retroversion that primarily occurred during the first three months. C-stem AMT subsided less during the first three months (p = 0.01), before stabilising at a subsidence rate similar to the Exeter stem from years one to two. The rate of migration into retroversion was slightly higher for C-stem AMT during the second year (p = 0.03). Whilst there were slight differences in movement patterns between the stems, the C-stem AMT exhibits good early clinical outcomes and displays a pattern of migration and bone remodelling that predicts good clinical performance. Cite this article: Bone Joint J 2015;97-B:755–61

Objectives: Nowadays estimating paediatric bone age is done using methods based on standards from the 50’s and 70’s. These methods are often difficult to perform, they require experience in the analysis of multiple bones and are based on subjective measures. Many times, the age calculated stands within a wide range of age interval. We investigate a new method based on AP foot X-rays. Material and Methods: 971 radiographs taken from 220 paediatric patients (0–18 years old) were analyzed. 34 different ratios were designed by measuring ossification centres of the bones of the first and second foot rays. These ratios were statistically studied searching for the relation with variables as gender, laterality, foot pathology and forefoot formulae. Finally, regression lines and curves from each ratio were calculated as well as their correlation with chronological age. Results: The best suited correlations are obtained with the ratios calculated from the epiphysis of the proximal phalange of the first and second toes. With them, multiple regression analysis is able to establish an equation that estimates bone age, with a chronological age correlation of 0,86 for general population, 0,85 for boys and 0,90 for girls (p< 0,01). It is applicable for either feet, and valid for every forefoot formula or pathologic feet. Conclusions: This new method is designed to estimate bone age in children using either plain radiographs or digital images. The method is objective, precise, universal and easy to calculate. It proves a good correlation in children between 1 and 13 years old. It is based on a modern population and adjusted with lineal regression equations to both genders

We assessed the Japanese specific bone age standard with Tanner-Whitehouse 2 (TW2) method for the evaluation of skeletal maturity in adolescent scoliosis. TW2 bone age was investigated by the left hand-wrist X-rays of 120 girls with adolescent scoliosis. Their chronological age ranged from 10.2 to 19.0 years. Because Risser’s sign is uncertain between Risser IV and V, for comparison of TW2 bone age with Risser’s sign, we classified apophyses that with an apparent narrowing of cartilage and that with a partial fusion as the later of Risser IV. In addition, clinical courses of the skeletal matured cases (adult bones) in 6 months before investigation were reviewed retrospectively. Even or less than 5 degrees change of Cobb’s angle was evaluated as unchanged. Furthermore, bone age distribution of immature cases was also reviewed for comparision of the unchanged group with the progressive group. None was evaluated as adult bone in the stage from Risser 0 to III. The rate of adult bone which was shown in Risser IV was 43.5%, but 88.9% was in the later of IV. 95.8% of Risser V was already adult bone. Moreover, 93.1% of adult bone was unchanged in their clinical courses. Remaining 4 cases (6.9%) was progressive, but had not progressed in the following 6 months. Bone ages of the progressive immature group distributed in the range from 11.7 to 13.9 years. Those of the unchanged immature group distributed mainly over 13.1 years. Although it is necessary to follow the immature longitudinally, adult bone appeared almost in the later of Risser IV, and appeared earlier than Risser V. And Cobb’s angle may become unchanged before adult bone. At least adult bone would be an indicator between Risser IV and V

Objectives. In total hip arthroplasty (THA), the cementless, tapered-wedge stem design contributes to achieving initial stability and providing optimal load transfer in the proximal femur. However, loading conditions on the femur following THA are also influenced by femoral structure. Therefore, we determined the effects of tapered-wedge stems on the load distribution of the femur using subject-specific finite element models of femurs with various canal shapes. Patients and Methods. We studied 20 femurs, including seven champagne flute-type femurs, five stovepipe-type femurs, and eight intermediate-type femurs, in patients who had undergone cementless THA using the Accolade TMZF stem at our institution. Subject–specific finite element (FE) models of pre- and post-operative femurs with stems were constructed and used to perform FE analyses (FEAs) to simulate single-leg stance. FEA predictions were compared with changes in bone mineral density (BMD) measured for each patient during the first post-operative year. Results. Stovepipe models implanted with large-size stems had significantly lower equivalent stress on the proximal-medial area of the femur compared with champagne-flute and intermediate models, with a significant loss of BMD in the corresponding area at one year post-operatively. Conclusions. The stovepipe femurs required a large-size stem to obtain an optimal fit of the stem. The FEA result and post-operative BMD change of the femur suggest that the combination of a large-size Accolade TMZF stem and stovepipe femur may be associated with proximal stress shielding. Cite this article: M. Oba, Y. Inaba, N. Kobayashi, H. Ike, T. Tezuka, T. Saito. Effect of femoral canal shape on mechanical stress distribution and adaptive bone remodelling around a cementless tapered-wedge stem. Bone Joint Res 2016;5:362–369. DOI: 10.1302/2046-3758.59.2000525

We measured bone mineral density (BMD) in the proximal femur by dual-energy X-ray absorptiometry (DEXA) in 20 patients after cemented total hip arthroplasty over a period of one year. We found a statistically significant reduction in periprosthetic BMD after six months on the medial side and on the lateral side adjacent to the mid and distal thirds of the prosthesis. At one year after operation there was a mean 6.7% reduction in BMD in the region of the calcar and a mean 5.3% increase in BMD in the femoral shaft distal to the tip of the implant. These changes reflect a pattern of reduced stress in the proximal femur and increased stress around the tip of the prosthesis. They support current concepts of bone remodelling in the proximal femur in response to prosthetic implantation

Introduction: The assessment of bone age using the standard Gruel and Pyle chart based on hand and wrist radiographs is usually carried out by Senior Radiologists. We performed a study to look at both intra and inter observer variability with different grades of clinicians. Materials and Methods: 30 sets of wrist radiographs were selected at random. The investigators included a Senior Radiographer, a Consultant and Registrar Radiologist an Orthopaedic Consultant and Senior Orthopaedic Fellow. Discussion: The Radiology team appear to be more consistent in their readings for the assessment of skeletal bone age than the Orthopaedic team. Howevr, it is interesting to note that although the Orthopaedic team are less consistent, when looking at the inter-observer variability, it suggests that both teams are equally well equipped to perform the task. Conclusion: Our study suggests that we should not cross professional boundaries. Render unto Caeser what is Ceaser’s!

We used dual-energy x-ray absorptiometry (DEXA) to evaluate the extent of periprosthetic bone remodelling around a prosthesis for distal femoral reconstruction, the Kotz modular femoral tibial replacement (KMFTR; Howmedica, Rutherford, New Jersey). A total of 23 patients was entered into the study which had four parts: 1) 17 patients were scanned three times on both the implant and contralateral legs to determine whether the precision of DEXA measurements was adequate to estimate bone loss surrounding the anchorage piece of the KMFTR; 2) in 23 patients the bone mineral density (BMD) in different regions of interest surrounding the diaphyseal anchorage was compared with that of the contralateral femur at the same location to test whether there was consistent evidence of loss of BMD adjacent to the prosthetic stem; 3) in 12 patients sequential studies were performed about one year apart to compare bone loss; and 4) bone loss was compared in ten patients with implants fixed by three screws and in 13 without screws. The mean coefficients of variation (SD/mean) for the 17 sets of repeated scans ranged from 2.9% to 7.8% at different regions of interest in the KMFTR leg and from 1.4% to 2.5% in the contralateral leg. BMD was decreased in the KMFTR leg relative to the contralateral limb and the percentage of BMD loss in general increased as the region of interest moved distally in the femur. Studies done after one year showed no consistent pattern of progressive bone loss between the two measurements. The ten patients with implants fixed by screws were found to have a mean loss of BMD of 42% in the most distal part of the femur, while the 13 without screw fixation had a mean loss of 11%. DEXA was shown to have adequate precision to evaluate loss of BMD around the KMFTR. This was evident relative to the contralateral leg in all patients and generally increased in the most distal part of the femur. In general, it stabilised between two measurements taken one year apart and was greater surrounding implants fixed by cross-locking screws

Aims. The aim of this study was to evaluate the clinical and radiological outcome of using an anatomical short-stem shoulder prosthesis to treat primary osteoarthritis of the glenohumeral joint. Patients and Methods. A total of 66 patients (67 shoulders) with a mean age of 76 years (63 to 92) were available for clinical and radiological follow-up at two different timepoints (T1, mean 2.6 years, . sd. 0.5; T2, mean 5.3 years,. sd. 0.7). Postoperative radiographs were analyzed for stem angle, cortical contact, and filling ratio of the stem. Follow-up radiographs were analyzed for timing and location of bone adaptation (cortical bone narrowing, osteopenia, spot welds, and condensation lines). The bone adaptation was classified as low (between zero and three features of bone remodelling around the humeral stem) or high (four or more features). Results. The mean Constant score improved significantly from 28.5 (. sd. 11.6) preoperatively to 75.5 (. sd. 8.5) at T1 (p < 0.001) and remained stable over time (T2: 76.6, . sd. 10.2). No stem loosening was seen. High bone adaptation was present in 42% of shoulders at T1, with a slight decrease to 37% at T2. Cortical bone narrowing and osteopenia in the region of the calcar decreased from 76% to 66% between T1 and T2. Patients with high bone adaptation had a significantly higher mean filling ratio of the stem at the metaphysis (0.60, . sd. 0.05 vs 0.55, . sd. 0.06; p = 0.003) and at the diaphysis (0.65 . sd. 0.05 vs 0.60 . sd. 0.05; p = 0.007). Cortical contact of the stem was also associated with high bone adaptation (14/25 shoulders, p = 0.001). The clinical outcome was not influenced by the radiological changes. Conclusion. Total shoulder arthroplasty using a short-stem humeral component resulted in good clinical outcomes with no evidence of loosening. However, approximately 40% of the shoulders developed substantial bone loss in the proximal humerus at between four and seven years of follow-up. Cite this article: Bone Joint J 2018;100-B:603–9

Objectives. Bisphosphonates are widely used as first-line treatment for primary and secondary prevention of fragility fractures. Whilst they have proved effective in this role, there is growing concern over their long-term use, with much evidence linking bisphosphonate-related suppression of bone remodelling to an increased risk of atypical subtrochanteric fractures of the femur (AFFs). The objective of this article is to review this evidence, while presenting the current available strategies for the management of AFFs. Methods. We present an evaluation of current literature relating to the pathogenesis and treatment of AFFs in the context of bisphosphonate use. Results. Six broad themes relating to the pathogenesis and management of bisphosphonate-related AFFs are presented. The key themes in fracture pathogenesis are: bone microdamage accumulation; altered bone mineralisation and altered collagen formation. The key themes in fracture management are: medical therapy and surgical therapy. In addition, primary prevention strategies for AFFs are discussed. Conclusions. This article presents current knowledge about the relationship between bisphosphonates and the development of AFFs, and highlights key areas for future research. In particular, studies aimed at identifying at-risk subpopulations and organising surveillance for those on long-term therapy will be crucial in both increasing our understanding of the condition, and improving population outcomes. Cite this article: N. Kharwadkar, B. Mayne, J. E. Lawrence, V. Khanduja. Bisphosphonates and atypical subtrochanteric fractures of the femur. Bone Joint Res 2017;6:144–153. DOI: 10.1302/2046-3758.63.BJR-2016-0125.R1

Aims

The management of periprosthetic joint infection (PJI) remains a major challenge in orthopaedic surgery. In this study, we aimed to characterize the local bone microstructure and metabolism in a clinical cohort of patients with chronic PJI.

The aims of this study were to examine the repeatability of measurements of bone mineral density (BMD) around a cemented polyethylene Charnley acetabular component using dual-energy x-ray absorptiometry and to determine the longitudinal pattern of change in BMD during the first 24 months after surgery.

The precision of measurements of BMD in 19 subjects ranged from 7.7% to 10.8% between regions, using a four-region-of-interest model. A longitudinal study of 27 patients demonstrated a transient decrease in net pelvic BMD during the first 12 months, which recovered to baseline at 24 months. The BMD in the region medial to the dome of the component reduced by between 7% and 10% during the first three months, but recovered to approximately baseline values by two years.

Changes in BMD in the pelvis around cemented acetabular components may be measured using dual-energy x-ray absorptiometry. Bone loss after insertion of a cemented Charnley acetabular component is small, transient and occurs mainly at the medial wall of the acetabulum. After two years, bone mass returns to baseline values, with a pattern suggesting a uniform transmission of load to the acetabulum.

Displaced fractures of the distal radius in children are usually reduced under sedation or general anaesthesia to restore anatomical alignment before the limb is immobilized. However, there is growing evidence of the ability of the distal radius to remodel rapidly, raising doubts over the benefit to these children of restoring alignment. There is now clinical equipoise concerning whether or not young children with displaced distal radial fractures benefit from reduction, as they have the greatest ability to remodel. The Children’s Radius Acute Fracture Fixation Trial (CRAFFT), funded by the National Institute for Health and Care Research, aims to definitively answer this question and determine how best to manage severely displaced distal radial fractures in children aged up to ten years.

Cite this article: Bone Joint J 2024;106-B(1):16–18.

We investigated the implant-bone interface around one design of femoral stem, proximally coated with either a plasma-sprayed porous coating (plain porous) or a hydroxyapatite porous coating (porous HA), or which had been grit-blasted (Interlok). Of 165 patients implanted with a Bimetric hip hemiarthroplasty (Biomet, Bridgend, UK) specimens were retrieved from 58 at post-mortem.

We estimated ingrowth and attachment of bone to the surface of the implant in 21 of these, eight plain porous, seven porous HA and six Interlok, using image analysis and light morphometric techniques. The amount of HA coating was also quantified.

There was significantly more ingrowth (p = 0.012) and attachment of bone (p > 0.05) to the porous HA surface (mean bone ingrowth 29.093 ± 2.019%; mean bone attachment 37.287 ± 2.489%) than to the plain porous surface (mean bone ingrowth 21.762 ± 2.068%; mean bone attachment 18.9411 ± 1.971%). There was no significant difference in attachment between the plain porous and Interlok surfaces. Bone grew more evenly over the surface of the HA coating whereas on the porous surface, bone ingrowth and attachment occurred more on the distal and medial parts of the coated surface. No significant differences in the volume of HA were found with the passage of time.

This study shows that HA coating increases the amount of ingrowth and attachment of bone and leads to a more even distribution of bone over the surface of the implant. This may have implications in reducing stress shielding and limiting osteolysis induced by wear particles.

Metabolic bone diseases, such as osteoporosis and osteopetrosis, result from an imbalanced bone remodeling process. In vitro bone models are often used to investigate either bone formation or resorption independently, while in vivo, these processes are coupled. Combining these processes in a co-culture is challenging as it requires finding the right medium components to stimulate each cell type involved without interfering with the other cell type's differentiation. Furthermore, differentiation stimulating factors often comprise growth factors in supraphysiological concentrations, which can overshadow the cell-mediated crosstalk and coupling. To address these challenges, we aimed to recreate the physiological bone remodeling process, which follows a specific sequence of events starting with cell activation and bone resorption by osteoclasts, reversal, followed by bone formation by osteoblasts. We used a mineralized silk fibroin scaffold as a bone-mimetic template, inspired by bone's extracellular matrix composition and organization. Our model supported osteoclastic resorption and osteoblastic mineralization in the specific sequence that represents physiological bone remodeling. We also demonstrated how culture variables, such as different cell ratios, base media, and the use of osteogenic/osteoclast supplements, and the application of mechanical load, can be adjusted to represent either a high bone turnover system or a self-regulating system. The latter system did not require the addition of osteoclastic and osteogenic differentiation factors for remodeling, therefore avoiding growth factor use. Our in vitro model for bone remodeling has the potential to reduce animal experiments and advance in vitro drug development for bone remodeling pathologies like osteoporosis. By recreating the physiological bone remodeling cycle, we can investigate cell-cell and cell-matrix interactions, which are essential for understanding bone physiology and pathology. Furthermore, by tuning the culture variables, we can investigate bone remodeling under various conditions, potentially providing insights into the mechanisms underlying different bone disorders

Abstract. Objectives. Young patients receiving metallic bone implants after surgical resection of bone cancer require implants that last into adulthood, and ideally life-long. Porous implants with similar stiffness to bone can promote bone ingrowth and thus beneficial clinical outcomes. A mechanical remodelling stimulus, strain energy density (SED), is thought to be the primary control variable of the process of bone growth into porous implants. The sequential process of bone growth needs to be taken into account to develop an accurate and validated bone remodelling algorithm, which can be employed to improve porous implant design and achieve better clinical outcomes. Methods. A bone remodelling algorithm was developed, incorporating the concept of bone connectivity (sequential growth of bone from existing bone) to make the algorithm more physiologically relevant. The algorithm includes adaptive elastic modulus based on apparent bone density, using a node-based model to simulate local remodelling variations while alleviating numerical checkerboard problems. Strain energy density (SED) incorporating stress and strain effects in all directions was used as the primary stimulus for bone remodelling. The simulations were developed to run in MATLAB interfacing with the commercial FEA software ABAQUS and Python. The algorithm was applied to predict bone ingrowth into a porous implant for comparison against data from a sheep model. Results. The accuracy of the predicted bone remodelling was verified for standard loading cases (bending, torsion) against analytical calculations. Good convergence was achieved. The algorithm predicted good bone remodelling and growth into the investigated porous implant. Using the standard algorithm without connectivity, bone started to remodel at locations unconnected to any bone, which is physiologically implausible. The implementation of bone connectivity ensures the gradual process of bone growth into the implant pores from the sides. The bone connectivity algorithm predicted that the full remodelling required more time (approximately 50% longer), which should be considered when developing post-surgical rehabilitation strategies for patients. Both algorithms with and without bone connectivity implementation converged to same final stiffness (less than 0.01% difference). Almost all nodes reached the same density value, with only a limited number of nodes (less than 1%) in transition areas with a strong density gradient having noticeable differences. Conclusions. An improved bone remodelling algorithm based on strain energy density that modelled the sequential process of bone growth has been developed and tested. For a porous metallic bone implant the same final bone density distribution as for the original adaptive elasticity theory was predicted, with a slower and more fidelic process of growth from existing surrounding bone into the porous implant. Declaration of Interest. (b) declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported:I declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project

Introduction and Objective. Bone remodelling is a continuous process whereby osteocytes regulate the activity of osteoblasts and osteoclasts to repair loading-induced microdamage. While many in vitro studies have established the role of paracrine factors (e.g., RANKL/OPG) and cellular pathways involved in bone homeostasis, these techniques are generally limited to two-dimensional cell culture, which neglects the role of the native extracellular matrix in maintaining the phenotype of osteocyte. Recently, ex vivo models have been used to understand cell physiology and mechanobiology in the presence of the native matrix. Such approaches could be applicable to study the mechanisms of bone repair, whilst also enabling exploration of biomechanical cues. However, to date an ex vivo model of bone remodelling in cortical bone has not been developed. In this study, the objective was to develop an ex vivo model where cortical bone was subjected to cyclic strains to study the remodelling of bone. Materials and Methods. Ex vivo model of bone remodelling induced by cyclic loading: At the day of culling, beam-shape bovine bone samples were cut and preserved in PBS + 5% Pen/Strep + 2 mM L-Glut overnight at 37°C. Cyclic strains were applied with a three-point bend system to induce damage with a regime at 16.66 mm/min for 5,000 cycles in sterile PBS in Evolve® bags (maximum strain 6%). A control group was cultured under static conditions. Metabolic activity: Alamar Blue assays were performed after 1 and 7 days of ex vivo culture for each group (Static, Loaded) and normalized to weight. Bone remodelling: ALP activity was assessed in the media at day 1 and 7. After 24 hours cell culture conditioned media (CM) was collected from each group and stored at −80°C. RAW264.7 cells were cultured with CM for 6 days, after which the samples were stained for TRAP, to determine osteoclastogenesis, and imaged. Histomorphometry: Samples were cultured with calcein for 3 days to label bone formation between day 4 and 7. Fluorescent images were captured at day 7. μCT scanning was performed at 3 μm resolution after labelling samples with BaSO. 4. precipitate to quantify bone damage. Results. Bone was sectioned and cultured to maintain live osteoblasts and osteocytes. CM that was obtained 24 hours after cyclic loading and added to RAW264.7 cells cultures, resulted in significantly increased osteoclastogenic potential compared to that from static samples (4.245±1.65% vs 0.88±0.48%, p<0.001). Calcein and HE staining indicated the presence of structures similar to bone remodelling cones in both groups after 7 days of culture. Also, 7 days post-loading, matrix microdamage in the stimulated area, detected with the BaSO. 4. precipitate, were not significantly increased under the load point in loaded samples (0.11±0.05% of bone volume), while at the support areas it was significantly higher (0.2387±0.06%, p<0.001) compared to the static (0.062±0.02%). Conclusions. This study demonstrates that (1) cyclic strains applied on ex vivo bovine cortical bone successfully induced remodelling as characterized by the formation of bone resorption cones, along with an increase of osteoclast formation, and (2) there was an induction of microdamage post loading as shown by the significant increases in microdamage labelled. This supports previous in vivo studies with an increase in osteoclastogenesis up to 7 days post loading. This is the first evidence of the development of an ex vivo model to study osteon remodelling that could be applied to study bone physiology and repair

The effect of high-fat diet and testosterone replacement therapy upon bone remodelling was investigated in orchiectomised male APOE-/- mice. Mice were split in to three groups: sham surgery + placebo treatment (control, n=9), orchiectomy plus placebo treatment (n=8) and orchiectomy plus testosterone treatment (n=10). Treatments were administered via intramuscular injection once a fortnight for 17 weeks before sacrifice at 25 weeks of age. Tibiae were scanned ex-vivo using µCT followed by post-analysis histology and immunohistochemistry. Previously presented µCT data demonstrated orchiectomised, placebo treated mice exhibited significantly reduced trabecular bone volume, number, thickness and BMD compared to control mice despite no significant differences in body weight. Trabecular parameters were rescued back to control levels in orchiectomised mice treated with testosterone. No significant differences were observed in the cortical bone. Assessment of TRAP stained FFPE sections revealed no significant differences in osteoclast or osteoblast number along the endocortical surface. IHC assessment of osteoprotegerin (OPG) expression in osteoblasts is to be quantified alongside markers of osteoclastogenesis including RANK and RANKL. Results support morphological analysis of cortical bone where no change in cortical bone volume or density between groups is in line with no significant change in osteoblast or osteoclast number and percentage across all three groups. Future work will include further IHC assessment of bone remodelling and adiposity, as well as utilisation of mechanical testing to establish the effects of observed morphological differences in bone upon mechanical properties. Additionally, the effects of hormone treatments upon murine-derived bone cells will be investigated to provide mechanistic insights

Aims. Knee osteoarthritis (OA) involves a variety of tissues in the joint. Gene expression profiles in different tissues are of great importance in order to understand OA. Methods. First, we obtained gene expression profiles of cartilage, synovium, subchondral bone, and meniscus from the Gene Expression Omnibus (GEO). Several datasets were standardized by merging and removing batch effects. Then, we used unsupervised clustering to divide OA into three subtypes. The gene ontology and pathway enrichment of three subtypes were analyzed. CIBERSORT was used to evaluate the infiltration of immune cells in different subtypes. Finally, OA-related genes were obtained from the Molecular Signatures Database for validation, and diagnostic markers were screened according to clinical characteristics. Quantitative reverse transcription polymerase chain reaction (qRT‐PCR) was used to verify the effectiveness of markers. Results. C1 subtype is mainly concentrated in the development of skeletal muscle organs, C2 lies in metabolic process and immune response, and C3 in pyroptosis and cell death process. Therefore, we divided OA into three subtypes: bone remodelling subtype (C1), immune metabolism subtype (C2), and cartilage degradation subtype (C3). The number of macrophage M0 and activated mast cells of C2 subtype was significantly higher than those of the other two subtypes. COL2A1 has significant differences in different subtypes. The expression of COL2A1 is related to age, and trafficking protein particle complex subunit 2 is related to the sex of OA patients. Conclusion. This study linked different tissues with gene expression profiles, revealing different molecular subtypes of patients with knee OA. The relationship between clinical characteristics and OA-related genes was also studied, which provides a new concept for the diagnosis and treatment of OA. Cite this article: Bone Joint Res 2023;12(12):702–711

Femoroacetabular impingement (FAI) results from a morphological deformity of the hip and is associated with osteoarthritis (OA). Increased bone mineral density (BMD) is observed in the antero-superior acetabulum rim where impingement occurs. It is hypothesized that the repeated abnormal contact leads to damage of the cartilage layer, but could also cause a bone remodelling response according to Wolff's Law. Thus the goal of this study was to assess the relationship between bone metabolic activity measured by PET and BMD measured in CT scans. Five participants with asymptomatic cam deformity, three patients with uni-lateral symptomatic cam FAI and three healthy controls were scanned in a 3T PET-MRI scanner following injection with [18F]NaF. Bone remodelling activity was quantified with Standard Uptake Values (SUVs). SUVmax was analyzed in the antero-superior acetabular rim, femoral head and head-neck junction. In these same regions, BMD was calculated from CT scans using the calibration phantom included in the scan. The relationship between SUVmax and BMD from corresponding regions was assessed using the coefficient of determination (R. 2. ) from linear regression. High bone activity was seen in the cam deformity and acetabular rim. SUVmax was negatively correlated with BMD in the antero-superior region of the acetabulum (R. 2. =0.30, p=0.08). SUVmax was positively correlated with BMD in the antero-superior head-neck junction of the femur (R. 2. =0.359, p=0.067). Correlations were weak in other regions. Elevated bone turnover was seen in patients with a cam deformity but the relationship to BMD was moderate. This study demonstrates a pathomechanism of hip degeneration associated with FAI deformities, consistent with Wolff's law and the proposed mechanical cause of hip degeneration in FAI. [18F]-NaF PET SUV may be a biomarker of degeneration, especially in early stages of degeneration, when joint preservation surgery is likely to be the most successful

The success of cementless orthopaedic implants relies on bony ingrowth and active bone remodelling. Much research effort is invested to develop implants with controllable surface roughness and internal porous architectures that encourage these biological processes. Evaluation of these implants requires long-term and costly animal studies, which do not always yield the desired outcome requiring iteration. The aim of our study is to develop a cost-effective method to prescreen design parameters prior to animal trials to streamline implant development and reduce live animal testing burden. Ex vivo porcine cancellous bone cylinders (n=6, Ø20×12mm) were extracted from porcine knee joints with a computer-numerically-controlled milling machine under sterile conditions within 4 hours of animal sacrifice. The bone discs were implanted with Ø6×12mm additive manufactured porous titanium implants and were then cultured for 21days. Half underwent static culture in medium (DMEM, 10% FBS, 1% antibiotics) at 37°C and 5% CO. 2. The rest were cultured in novel high-throughput stacked configuration in a bioreactor that simulated physiological conditions after surgery: the fluid flow and cyclic compression force were set at 10ml/min and 10–150 N (1Hz,5000 cycles/day) respectively. Stains were administered at days 7 and 14. Samples were evaluated with widefield microscopy, scanning electron microscopy (SEM) and with histology. More bone remodelling was observed on the samples cultured within the bioreactor: widefield imaging showed more remodelling at the boundaries between the implant-bone interface, while SEM revealed immature bone tissue integration within the pores of the implant. Histological analysis confirmed these results, with many more trabecular struts with new osteoid formation on the samples cultured dynamically compared to static ones. Ex vivo bone can be used to analyse new implant technologies with lower cost and ethical impact than animal trial. Physiological conditions (load and fluid flow) promoted bone ingrowth and remodelling

Aims. Osteoarthritis (OA) is a common degenerative joint disease. The osteocyte transcriptome is highly relevant to osteocyte biology. This study aimed to explore the osteocyte transcriptome in subchondral bone affected by OA. Methods. Gene expression profiles of OA subchondral bone were used to identify disease-relevant genes and signalling pathways. RNA-sequencing data of a bone loading model were used to identify the loading-responsive gene set. Weighted gene co-expression network analysis (WGCNA) was employed to develop the osteocyte mechanics-responsive gene signature. Results. A group of 77 persistent genes that are highly relevant to extracellular matrix (ECM) biology and bone remodelling signalling were identified in OA subchondral lesions. A loading responsive gene set, including 446 principal genes, was highly enriched in OA medial tibial plateaus compared to lateral tibial plateaus. Of this gene set, a total of 223 genes were identified as the main contributors that were strongly associated with osteocyte functions and signalling pathways, such as ECM modelling, axon guidance, Hippo, Wnt, and transforming growth factor beta (TGF-β) signalling pathways. We limited the loading-responsive genes obtained via the osteocyte transcriptome signature to identify a subgroup of genes that are highly relevant to osteocytes, as the mechanics-responsive osteocyte signature in OA. Based on WGCNA, we found that this signature was highly co-expressed and identified three clusters, including early, late, and persistently responsive genes. Conclusion. In this study, we identified the mechanics-responsive osteocyte signature in OA-lesioned subchondral bone. Cite this article: Bone Joint Res 2022;11(6):362–370

Aims. Therapeutic agents that prevent chondrocyte loss, extracellular matrix (ECM) degradation, and osteoarthritis (OA) progression are required. The expression level of epidermal growth factor (EGF)-like repeats and discoidin I-like domains-containing protein 3 (EDIL3) in damaged human cartilage is significantly higher than in undamaged cartilage. However, the effect of EDIL3 on cartilage is still unknown. Methods. We used human cartilage plugs (ex vivo) and mice with spontaneous OA (in vivo) to explore whether EDIL3 has a chondroprotective effect by altering OA-related indicators. Results. EDIL3 protein prevented chondrocyte clustering and maintained chondrocyte number and SOX9 expression in the human cartilage plug. Administration of EDIL3 protein prevented OA progression in STR/ort mice by maintaining the number of chondrocytes in the hyaline cartilage and the number of matrix-producing chondrocytes (MPCs). It reduced the degradation of aggrecan, the expression of matrix metalloproteinase (MMP)-13, the Osteoarthritis Research Society International (OARSI) score, and bone remodelling. It increased the porosity of the subchondral bone plate. Administration of an EDIL3 antibody increased the number of matrix-non-producing chondrocytes (MNCs) in cartilage and exacerbated the serum concentrations of OA-related pro-inflammatory cytokines, including monocyte chemotactic protein-3 (MCP-3), RANTES, interleukin (IL)-17A, IL-22, and GROα. Administration of β1 and β3 integrin agonists (CD98 protein) increased the expression of SOX9 in OA mice. Hence, EDIL3 might activate β1 and β3 integrins for chondroprotection. EDIL3 may also protect cartilage by attenuating the expression of IL-1β-enhanced phosphokinase proteins in chondrocytes, especially glycogen synthase kinase 3 alpha/beta (GSK-3α/β) and phospholipase C gamma 1 (PLC-γ1). Conclusion. EDIL3 has a role in maintaining the cartilage ECM and inhibiting the development of OA, making it a potential therapeutic drug for OA. Cite this article: Bone Joint Res 2023;12(12):734–746

Knowledge of the premorbid glenoid shape and the morphological changes the bone undergoes in patients with glenohumeral arthritis can improve surgical outcomes in total and reverse shoulder arthroplasty. Several studies have previously used scapular statistical shape models (SSMs) to predict premorbid glenoid shape and evaluate glenoid erosion properties. However, current literature suggests no studies have used scapular SSMs to examine the changes in glenoid surface area in patients with glenohumeral arthritis. Therefore, the purpose of this study was to compare the glenoid articular surface area between pathologic glenoid cavities from patients with glenohumeral arthritis and their predicted premorbid shape using a scapular SSM. Furthermore, this study compared pathologic glenoid surface area with that from virtually eroded glenoid models created without influence from internal bone remodelling activity and osteophyte formation. It was hypothesized that the pathologic glenoid cavities would exhibit the greatest glenoid surface area despite the eroded nature of the glenoid and the medialization, which in a vault shape, should logically result in less surface area. Computer tomography (CT) scans from 20 patients exhibiting type A2 glenoid erosion according to the Walch classification [Walch et al., 1999] were obtained. A scapular SSM was used to predict the premorbid glenoid shape for each scapula. The scapula and humerus from each patient were automatically segmented and exported as 3D object files along with the scapular SSM from a pre-operative planning software. Each scapula and a copy of its corresponding SSM were aligned using the coracoid, lateral edge of the acromion, inferior glenoid tubercule, scapular notch, and the trigonum spinae. Points were then digitized on both the pathologic humeral and glenoid surfaces and were used in an iterative closest point (ICP) algorithm in MATLAB (MathWorks, Natick, MA, USA) to align the humerus with the glenoid surface. A Boolean subtraction was then performed between the scapular SSM and the humerus to create a virtual erosion in the scapular SSM that matched the erosion orientation of the pathologic glenoid. This led to the development of three distinct glenoid models for each patient: premorbid, pathologic, and virtually eroded (Fig. 1). The glenoid surface area from each model was then determined using 3-Matic (Materialise, Leuven, Belgium). Figure 1. (A) Premorbid glenoid model, (B) pathologic glenoid model, and (C) virtually eroded glenoid model. The average glenoid surface area for the pathologic scapular models was 70% greater compared to the premorbid glenoid models (P < 0 .001). Furthermore, the surface area of the virtual glenoid erosions was 6.4% lower on average compared to the premorbid glenoid surface area (P=0.361). The larger surface area values observed in the pathologic glenoid cavities suggests that sufficient bone remodelling exists at the periphery of the glenoid bone in patients exhibiting A2 type glenohumeral arthritis. This is further supported by the large difference in glenoid surface area between the pathologic and virtually eroded glenoid cavities as the virtually eroded models only considered humeral anatomy when creating the erosion. For any figures or tables, please contact the authors directly

Abstract. Cranial cruciate ligament (CrCL) disease/rupture is a highly prevalent orthopaedic disease in dogs and common cause of pain, lameness, and secondary joint osteoarthritis (OA). Previous experiments investigating the role of glutamate receptors (GluR) in arthritic degeneration and pain revealed that OA biomarkers assessing early bone turnover and inflammation, including osteoprotegerin (OPG) and the receptor activator of nuclear factor kappa-B ligand (RANKL) are more likely to be influenced by glutamate signalling. Moreover, interleukin-6 (IL-6) has a complex and potentially bi directional (beneficial and detrimental) effect, and it is a critical mediator of arthritic pain, OA progression and joint destruction. Objectives. 1) to recruit dogs undergoing CrCL disease/rupture surgery and obtain discarded synovial fluid (SF) and serum/plasma (ethics approval, RCVS:2017/14/Alves); 2) to quantify the biomarkers listed above in the SF and serum/plasma by enzyme linked immunosorbent assay (ELISA); 3) to assess radiographic OA at the time of surgery and correlate it with the biomarkers and clinical findings. Methods. Abnova, Abcam and AMSBIO ELISA kits were tested using a validation protocol relating the standard curve to a dilution series of SF and serum/plasma (1× to 1/50×), with and without SF hyaluronidase treatment to evaluate linearity, specificity and optimal dilutions. Validated ELISA kits were used to measure [IL-6], glutamate [glu], [RANKL] and [OPG] in SF and serum/plasma. For each dog, CrCL disease pre-operative lameness scores were graded as: (1) mild, (2) moderate (easily visible), (3) marked (encumbered), (4) non-weightbearing lameness. Blinded OA scoring was performed on radiographs [15–60, normal-severe OA]. Results. canine population (n=14) was of various breeds, aged between 2–10 years and weighing 17.1–45.5Kg; 42.86% male; 57.14% female; 83.33% males and 62.5% females were neutered. Lameness scores varied from 1 and 4 (average 2.07±1.12) and radiographic OA scores from 18 and 36 (average 27.86±5.11). Individual correlations in concentrations with respect to age, weight, lameness score (1–4) and OA scores (15–60) were tested. SF [glu] and lameness score were inversely correlated with higher levels of lameness corresponding to lower SF [glu] (P=0.0141). SF [RANKL] inversely correlated with weight (P=0.0045) and lameness score (P=0.0135), and serum [RANKL] inversely correlated with weight (P=0.0437). There was also a negative correlation between SF and serum [OPG] and weight (P=0.0165 and P=0.0208, respectively). No other significant correlations were detected. Overall, [glu] and [IL-6] are increased in SF compared to serum/plasma, by 12.84 and 1.28, respectively, whereas all the remaining biomarkers are higher (2–3 times) in the serum/plasma compared to SF. Principal component analysis (PCA) and Pearson correlation coefficient matrix [IL-6/glu/RANKL/OPG] (n=7) showed SF [IL-6] correlates with SF [glu] (rs=0.64) and strong positive correlations between SF/serum [RANKL] and SF/serum [OPG] (rs 0.68–0.96). Conclusions. Dogs with CrCL disease show an association between the bone remodelling markers RANKL and OPG, and the inflammatory cytokine IL-6, and to a lesser extent SF [glu]. Therapeutics targeting bone remodelling, IL-6 or GluR/[glu] may be of interest for the management of OA in dogs. Declaration of Interest. (b) declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported:I declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project

Aims. The aim of this study was to compare the mid-term patient-reported outcome, bone remodelling, and migration of a short stem (Collum Femoris Preserving; CFP) with a conventional uncemented stem (Corail). Methods. Of 81 patients who were initially enrolled, 71 were available at five years’ follow-up. The outcomes at two years have previously been reported. The primary outcome measure was the clinical result assessed using the Oxford Hip Score (OHS). Secondary outcomes were the migration of the stem, measured using radiostereometric analysis (RSA), change of bone mineral density (BMD) around the stem, the development of radiolucent lines, and additional patient-reported outcome measures (PROMs). Results. There were no statistically significant differences between the groups regarding PROMs (median OHS (CFP 45 (interquartile range (IQR) 35 to 48); Corail 45 (IQR 40 to 48); p = 0.568). RSA showed stable stems in both groups, with little or no further subsidence between two and five years. Resorption of the femoral neck was evident in nine patients in the CFP group and in none of the 15 Corail stems with a collar that could be studied. Dual X-ray absorbiometry showed a significantly higher loss of BMD in the proximal Gruen zones in the CFP group (mean changes in BMD: Gruen zone 1, CFP -9.5 (95% confidence interval (CI) -14.8 to -4.2), Corail 1.0 (95% CI 3.4 to 5.4); Gruen zone 7, CFP -23.0 (95% CI -29.4 to -16.6), Corail -7.2 (95% CI -15.9 to 1.4). Two CFP stems were revised before two years’ follow-up due to loosening, and one Corail stem was revised after two years due to chronic infection. Conclusion. The CFP stem has a similar clinical outcome and subsidence pattern when compared with the Corail stem. More pronounced proximal stress-shielding was seen with the CFP stem, suggesting diaphyseal fixation, and questioning its femoral neck-sparing properties in the long term. Cite this article: Bone Joint J 2022;104-B(5):581–588

Introduction. Direct skeletal attachment of prosthetic limbs, commonly known as osseointegration (“OI”), is being investigated by our team with the goal of safely introducing this technology into the United States for human use. OI technology allows for anchorage of prosthetic devices directly to bone using an intramedullary stem. For OI to be effective and secure, bone ingrowth and remodeling around the implant must be achieved. Physicians need an effective way to measure bone remodeling in order to make informed decisions on prescribed loading. This work describes methodology that was developed that utilizes computed tomography (CT) imaging as a tool for analyzing bone remodeling around an osseointegrated implant. Method. A subject implanted with a new Percutaneous Osseointegrated Prosthesis (POP) (DJO Surgical, Austin, TX) had CTs taken of their residual femur at 6-weeks and 12-months post-op in a FDA Early Feasibility Study with Institutional Review Board approval. Three-dimensional models of the femur were created from dicom files of the CT slices using Mimics (v21.0, Materialise, Leuven, Belgium). Each scan was segmented into four objects: cortical bone, medullary cavity, total volume (cortical bone plus the medullary cavity) and endoprosthetic stem (Fig. 1). Following segmentation, models were uploaded to 3-Matic Research (v13.0, Materialise, Leuven, Blegium) in STL format for alignment to a common world coordinate system (Fig. 2). A common origin was set by taking the average distance between planes of the femoral head and the greater trochanter. Once aligned to the coordinate system, biomechanical length (BML) was calculated from the proximal origin to the distal end of the amputated femur. BML and STLs of the aligned medullary cavity and femur volume were entered into custom Matlab code designed to measure cortical and medullary morphology in transverse cross sections of the femur. Morphology data from 6-weeks and 12-month time points were compared in order to determine if bone remodeling around the POP implant could be detected using these methods. Results. Comparing longitudinal data from post-operative visits suggests that important indicators of bone remodeling around the device could be detected (Fig 3). One year after implantation of the POP device the medullary perimeter and area had minimal % differences (−1.5 and 2.2) from the 6-week visit, validating that consistent alignment of the femoral model was achieved between scans from different time points. The cortical area, cortical perimeter, and cortical thickness around the POP implant showed positive percent changes at the 12-months of 19.44%, 4.04% and 14.36% respectively, with the largest increases observed at the the distal end for each parameter. These increases in cortex morphology values indicate bone changes were identified around the endoprosthetic stem of the implant. Discussion/Conclusion. This pilot study utilized CT imaging as a tool for analyzing bone remodeling around a new osseointegrated device. These methods can be performed quickly and accurately and have the potential for use in monitoring bone remodeling. CT scans from additional subjects are being analyzed to further validate and optimize these methods for clinical use. This study described an investigational device, limited by federal law to investigational use. No long-term data exists about its performance. For any figures or tables, please contact the authors directly

In conventional DXA (Dual-energy X-ray Absorptiometry) analysis, pixel bone mineral density (BMD) is often averaged at the femoral neck. Neck BMD constitutes the basis for osteoporosis diagnosis and fracture risk assessment. This data averaging, however, limits our understanding of localised spatial BMD patterns that could potentially enhance fracture prediction. DXA region free analysis (RFA) is a validated toolkit for pixel-level BMD analysis. We have previously deployed this toolkit to develop a spatio-temporal atlas of BMD ageing in the femur. This study aims first to introduce bone age to reflect the overall bone structural evolution with ageing, and second to quantify fracture-specific patterns in the femur. The study dataset comprised 4933 femoral DXA scans from White British women aged 75 years or older. The total number of fractures was 684, of which 178 were reported at the hip within a follow-up period of five years. BMD maps were computed using the RFA toolkit. For each BMD map, bone age was defined as the age for which the L2-norm between the map and the median atlas at that age is minimised. Next, bone maps were normalised for the estimated bone age. A t-test followed by false discovery rate (FDR) analysis was applied to compare between fracture and non-fracture groups. Excluding the ageing effect revealed subtle localised patterns of loss in BMD oriented in the same direction as principal tensile curves. A new score called f-score was defined by averaging the normalised pixel BMD values over the region with FDR q-value less than 1e–6. The area under the curve (AUC) was 0.731 (95% confidence interval (CI)=0.689–0.761) and 0.736 (95% CI=0.694–0.769) for neck BMD and f-score. Combining bone age and f-score improved the AUC significantly by 3% (AUC=0.761, 95% CI=0.756–0.768) over the neck BMD alone (AUC=0.731, 95% CI=0.726–0.737). This technique shows promise in characterizing spatially-complex BMD changes, for which the conventional region-based technique is insensitive. DXA RFA shows promise to further improve fracture prediction using spatial BMD distribution

Introduction and Objective. The osteocyte, recognized as a major orchestrator of osteoblast and osteoclast activity, is the most important key player during bone remodeling processes. Imbalances that occur during bone remodeling, caused by hormone perturbations or alterations in mechanical loading, can induce bone disease as osteoporosis. Due to limited understanding of the underlying mechanisms, current therapies for osteoporosis cannot adequately address this imbalance because current studies of osteocytes rely on conventional cell culture that cannot recapitulate local in vivo microenvironments for the lack of control of the spatial/temporal distribution of cells and biomolecules. Microfluidics is the science and technology of microscale fluid manipulating and sensing and can help fill this gap. Materials and Methods. We used a microfluidic device to enable the culture of osteocyte-like cells (MLO-Y4 and MLO-A5) in a 3D fashion. Osteocytes were cultured in a perfused and 160 μm high channel and embedded in a bone-like extracellular matrix: osteocytes were embedded in a matrigel- and collagen-based hydrogel enriched with nanostructured hydroxypatite crystals (HA-NP) to mimic bone. To set up the best combination of matrigel enriched with Type I collagen we used fluorescent microspheres and confocal analysis. To evaluate the viability and the expression of osteocytic markers, we used live-dead assay amd immunofluorescent staining and confocal analysis combined with automated quantification. For mineralization, we performed alizarin red staining. Results. Osteocytes in the organ-on-a-chip model showed high viability and, in respect to 2D conventional cell cultures an increased differentiation, as assessed by a live-dead assay and the staining of the osteocytic markers connexin-43 and alkaline phosphatase and the increased mineralization activity. Furthermore, the addition of HA-NP significantly increased the formation of dendrite-like structures spreading through the xyz-axes, as assessed after G-actin immunofluorescence. Conclusions. Using a microfluidic device for MLO-Y4 and MLO-A5 cell cultures, compared to the 2D surfaces, we demonstrated a significant difference in cell differentiation and morphology. In particular, 3D cultures allowed the formation of 3D cell networks and the osteogenic phenotype. As a platform technology, this microfluidic device can function as a novel cell culture model that enables further studies of osteocytes and 3D co-culturing with other bone cells for the screening of anti-osteoporotic drugs

Aims. Using 90% of final height as a benchmark, we sought to develop a quick, quantitative and reproducible method of estimating skeletal maturity based on topographical changes in the distal femoral physis. Patients and Methods. Serial radiographs of the distal femoral physis three years prior to, during, and two years following the chronological age associated with 90% of final height were analyzed in 81 healthy children. The distance from the tip of the central peak of the distal femoral physis to a line drawn across the physis was normalized to the physeal width. Results. A total of 389 radiographs of the distal femur with corresponding Greulich and Pyle bone ages and known chronological ages were measured. Children reached 90% of final height at a mean age of 11.3 years (. sd. 0.8) for girls and 13.2 years (. sd. 0.6) for boys. Linear regression analysis showed higher correlation coefficent in predicting the true age at 90% of final height using chronological age + gender + central peak value (R. 2 . = 0.900) than chronological age + gender (R. 2.  = 0.879) and Greulich and Pyle bone age + gender (R. 2.  = 0.878). Conclusion. Chronological age + gender + central peak value provides more accurate prediction of 90% of final height compared with chronological age + gender and Greulich and Pyle bone age + gender. Cite this article: Bone Joint J 2018;100-B:1106–11

Osteoporosis is a worldwide disease resulting in the increase of bone fragility and enhanced fracture risk in adults. In the context of osteoporotic fractures, bone tissue engineering (BTE), i.e., the use of bone substitutes combining biomaterials, cells, and bone inducers, is a potential alternative to conventional treatments. Pre-clinical testing of innovative scaffolds relies on in vitro systems where the simultaneous presence of osteoblasts (OBs) and osteoclasts (OCs) is required to mimic their crosstalk and molecular cooperation for bone remodelling. To this aim, two composite materials based on type I collagen were developed, containing either strontium-enriched mesoporous bioactive glasses or rod-like hydroxyapatite nanoparticles. Following chemical crosslinking with genipin, the nanostructured materials were tested for 2–3 weeks with an indirect co-culture of human trabecular bone-derived OBs and buffy coat-derived OC precursors. The favourable structural and biological properties of the materials proved to successfully support the viability, adhesion, and differentiation of bone cells, encouraging a further investigation of the two bioactive systems as biomaterial inks for the 3D printing of more complex scaffolds for BTE

Aims. Aseptic loosening is a leading cause of uncemented arthroplasty failure, often accompanied by fibrotic tissue at the bone-implant interface. A biological target, neutrophil extracellular traps (NETs), was investigated as a crucial connection between the innate immune system’s response to injury, fibrotic tissue development, and proper bone healing. Prevalence of NETs in peri-implant fibrotic tissue from aseptic loosening patients was assessed. A murine model of osseointegration failure was used to test the hypothesis that inhibition (through Pad4-/- mice that display defects in peptidyl arginine deiminase 4 (PAD4), an essential protein required for NETs) or resolution (via DNase 1 treatment, an enzyme that degrades the cytotoxic DNA matrix) of NETs can prevent osseointegration failure and formation of peri-implant fibrotic tissue. Methods. Patient peri-implant fibrotic tissue was analyzed for NETs biomarkers. To enhance osseointegration in loose implant conditions, an innate immune system pathway (NETs) was either inhibited (Pad4-/- mice) or resolved with a pharmacological agent (DNase 1) in a murine model of osseointegration failure. Results. NETs biomarkers were identified in peri-implant fibrotic tissue collected from aseptic loosening patients and at the bone-implant interface in a murine model of osseointegration failure. Inhibition (Pad4-/-) or resolution (DNase 1) of NETs improved osseointegration and reduced fibrotic tissue despite loose implant conditions in mice. Conclusion. This study identifies a biological target (NETs) for potential noninvasive treatments of aseptic loosening by discovering a novel connection between the innate immune system and post-injury bone remodelling caused by implant loosening. By inhibiting or resolving NETs in an osseointegration failure murine model, fibrotic tissue encapsulation around an implant is reduced and osseointegration is enhanced, despite loose implant conditions. Cite this article: Bone Joint J 2021;103-B(7 Supple B):135–144

INTRODUCTION. Hip resurfacing offers a more bone conserving solution than total hip replacement (THR) but currently has limited clinical indications related to some poor design concepts and metal ion related issues. Other materials are currently being investigated based on their successful clinical history in THR such as Zirconia Toughened Alumina (ZTA, Biolox Delta, CeramTec, Germany) which has shown low wear rates and good biocompatibility but has previously only been used as a bearing surface in THR. A newly developed direct cementless fixation all-ceramic (ZTA) resurfacing cup offers a new solution for resurfacing however ZTA has a Young's modulus approximately 1.6 times greater than CoCr - such may affect the acetabular bone remodelling. This modelling study investigates whether increased stress shielding may occur when compared to a CoCr resurfacing implant with successful known clinical survivorship. METHODS. A finite element model of a hemipelvis constructed from CT scans was used and virtually reamed to a diameter of 58mm. Simulations were conducted and comparisons made of the ‘intact’ acetabulum and ‘as implanted’ with monobloc cups made from CoCr (Adept®, MatOrtho Ltd, UK) and ZTA (ReCerf ™, MatOrtho Ltd. UK) orientated at 35° inclination and 20° anteversion. The cups were loaded with 3.97kN representing a walking load of 280% for an upper bound height patient with a BMI of 35. The cup-bone interface was assigned a coulomb slip-stick function with a coefficient of friction of 0.5. The percentage change in strain energy density between the intact and implanted states was used to indicate hypertrophy (increase in density) or stress shielding (decrease in density). RESULTS. Implanting both cups changed the strain distribution observed in the hemipelvis, Figure 1. The change in strain distribution was similar between materials and indicated a similar response from the bone, Figure 2. In both implanted cases, the inferior peri-acetabular bone around the implant indicated a reduction in bone strain. The bone remodelling distribution charts show that regardless of threshold remodelling stimulus level (75% in elderly, 50% in younger patients) the CoCr and ZTA cups were expected to produce the same bone response with only a small percentage of the bone in the hemipelvis indicating stress shielding or hypertrophy, Figure 3. DISCUSSION. Currently only metal cups are used for cementless fixation but improvements in design and technology have made it possible to engineer a thin-walled, direct fixation, all-ceramic cup. Both CoCr and ZTA are an order of magnitude greater than the Young's modulus of cortical bone altering the bone strain but changing the material from CoCr to a stiffer ZTA did not change the expected bone remodelling response. Given the clinical history of metal cups without loosening due to bone remodelling, the study indicates that a ZTA cup should not lead to increased stress shielding and is potentially suitable for as a cementless cup for both resurfacing and THR. SIGNIFICANCE. An all-ceramic cup is unlikely to lead to increased stress shielding around the acetabulum due to the change in material. For any figures or tables, please contact the authors directly

Device-associated bacterial infections are a major and costly clinical challenge. This project aimed to develop a smart new biomaterial for implants that helps to protect against infection and inflammation, promote bone growth, and is biodegradable. Gallium (Ga) doped strontium-phosphate was coated on pure Magnesium (Mg) through a chemical conversion process. Mg was distributed in a graduated manner throughout the strontium-phosphate coating GaSrPO4, with a compact structure and a Ga-rich surface. We tested this sample for its biocompatibility, effects on bone remodeling and antibacterial activities including Staphylococcus aureus, S. epidermidis and E. coli - key strains causing infection and early failure of the surgical implantations in orthopaedics and trauma. Ga was distributed in a gradient way throughout the entire strontium-phosphate coating with a compact structure and a gallium-rich surface. The GaSrPO4 coating protected the underlying Mg from substantial degradation in minimal essential media at physiological conditions over 9 days. The liberated Ga ions from the coatings upon Mg specimens inhibited the growth of bacterial tested. The Ga dopants showed minimal interferences with the SrPO4 based coating, which boosted osteoblasts and undermined osteoclasts in in vitro co-cultures model. The results evidenced this new material may be further translated to preclinical trial in large animal model and towards clinical trial. Acknowledgements: Authors are grateful to the financial support from the Australian Research Council through the Linkage Scheme (ARC LP150100343). The authors acknowledge the facilities, and the scientific and technical assistance of the RMIT University and John Curtin School of Medical Research, Australian National University

Wear debris from implant interfaces is the major factor leading to periprosthetic osteolysis. Fibroblast-like synoviocytes (FLSs) populate the intimal lining of the synovium and are in direct contact with wear debris. This study aimed to elucidate the effect of Ti particles as wear debris on human FLSs and the mechanism by which they might participate in the bone remodeling process during periprosthetic osteolysis. FLSs were isolated from synovial tissue from patients, and the condition medium (CM) was collected after treating FLSs with sterilized Ti particles. The effect of CM was analyzed for the induction of osteoclastogenesis or any effect on osteogenesis and signaling pathways. The results demonstrated that Ti particles could induce activation of the NFκB signaling pathway and induction of COX-2 and inflammatory cytokines in FLSs. The amount of RANL in the conditioned medium collected from Ti particle-stimulated FLSs (Ti CM) showed the ability to stimulate osteoclast formation. The Ti CM also suppressed the osteogenic initial and terminal differentiation markers for osteoprogenitors, such as alkaline phosphate activity, matrix mineralization, collagen synthesis, and expression levels of Osterix, Runx2, collagen 1α, and bone sialoprotein. Inhibition of the WNT and BMP signaling pathways was observed in osteoprogenitors after the treatment with the Ti CM. In the presence of the Ti CM, exogenous stimulation by WNT and BMP signaling pathways failed to stimulate osteogenic activity in osteoprogenitors. Induced expression of sclerostin (SOST: an antagonist of WNT and BMP signaling) in Ti particletreated FLSs and secretion of SOST in the Ti CM were detected. Neutralization of SOST in the Ti CM partially restored the suppressed WNT and BMP signaling activity as well as the osteogenic activity in osteoprogenitors. Our results reveal that wear debris-stimulated FLSs might affect bone loss by not only stimulating osteoclastogenesis but also suppressing the bone-forming ability of osteoprogenitors. In the clinical setting, targeting FLSs for the secretion of antagonists like SOST might be a novel therapeutic approach for preventing bone loss during inflammatory osteolysis

Bone homeostasis is a highly regulated process involving pathways in bone as WNT, FGF or BMP, but also requiring support from surrounding tissues as vessels and nerves. In bone diseases, the bone-vessel-nerve triad is impacted. Recently, new players appeared as regulators of bone homeostasis: microRNAs (miRNA). Five miRNAs associated with osteoporotic fractures are already known, among which miR-125b is decreasing bone formation by downregulating human mesenchymal stem cells (hMSCs) differentiation. Other miRNAs, as miR-214 (in cluster with miR-199a), are secreted by osteoclasts to regulate osteoblasts and inhibit bone formation. This forms a very complex regulatory network. hMSCs and osteoblasts (n=3) were transfected with mimic/antagomiR of miR-125b, miR-199a-5p or miR-214, or with a scrambled miRNA (negative control) in osteogenic differentiation calcium-enriched medium (Ca++). Mineralization was assessed by Alizarin Red/CPC staining, miRNA expression by qPCR and protein by western blotting. Exposure of hMSCs or osteoblasts to Ca++ increased mineralization compared to basal medium. hMSCs transfected with miR-125b mimic in Ca++ presented less mineralization compared to scramble. This correlated with decreased levels of BMPR2 and RUNX2. hMSCs transfected with miR-125b inhibitor presented higher mineralization. Interestingly, hMSCs transfected with miR-214 mimic in Ca++ presented no mineralization while miR-214 inhibitor increased mineralization. No differences were observed in hMSCs transfected with miR-199a-5p modulators. On the contrary, osteoblasts transfected with miR-199a-5p mimic present less mineralization than scrambled-transfected and same was observed for miR-214 and miR-125b mimics. We highlight that miR-125b and miR-214 decrease mineralization of hMSCs in calcium-enriched medium. We noticed that miR-199a-5p is able to regulate mineralization in osteoblasts but not in hMSCs suggesting that this effect is cell-specific. Interestingly, the cluster miR-199a/214 is known as modulator of vascular function and could thus contribute to bone remodeling via different ways. With this work we slightly open the door to possible therapeutic approaches for bone diseases

We had previously reported on early outcomes on a new fluted, titanium, monobloc stem with a three degree taper that has been designed for challenging femoral reconstruction in the setting of extensive bone loss. The aim of this study was to report its mid-term clinical and radiographic outcomes. This is a retrospective review of prospectively collected data carried out at a single institution between Jan 2017 and Dec 2019. 85 femoral revisions were performed using a new tapered, fluted, titanium, monobloc (TFTM) revision stem. Complications, clinical and radiographic data were obtained from medical records and a locally maintained database. Clinical outcomes were assessed using the Oxford Hip Score (OHS) and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). All post-operative radiographs were analysed for subsidence, osteolysis and femoral cortical bone remodelling. Mean follow-up was 60 months (range 28–84 months). Subsidence of 1.2 mm was noted in one patient. No cases of clinically significant subsidence (10 mm) were observed. At final follow-up, a statistically significant improvement was noted in functional outcome scores. The mean OHS preoperatively and at final follow-up were 24 (SD 13) and 42 (SD15). p = 0.04 mean difference 18 (95% CI 15–22). The mean WOMAC scores preoperatively and at final follow-up were 62 (SD23) and 88 (SD7) respectively (p < 0.001, mean difference 26; 95% CI 21–34). No stem fractures were noted within the follow-up period. Two patients had revision of the stem's one for infection and another for persistent pain. Positive mid-term clinical and radiological outcomes have been observed with this tapered, fluted, titanium, monobloc stem. Based on these results, this implant may be considered as a viable option in the majority of uncemented femoral revisions

Low-energy fractures complications are a major public health issue that make osteoporosis even worse. In sub-Saharan Africa, the prevalence of osteoporosis varies from 18.2% to 65.8%. There was no change in bone mineral density between HIV-infected and non-HIV-infected women in Sub-Saharan Africa, where HIV is widespread. Other investigations that demonstrated that HIV-infected people had poor BMD both before and after starting anti-retroviral treatment did not consistently show a low BMD finding. Inflammation-mediated bone remodelling has been associated with low BMD in HIV-infected patients. Antiretroviral Therapy has been demonstrated to exacerbate bone loss in addition to the pre-existing intrinsic risk of developing osteoporosis. Question: Is there loss of bone in HIV-infected patients before initiating ART?. The patients who were HIV-positive and enrolled in the ADVANCE research were retrospectively reviewed on a desk. All of the 1053 individuals in the ADVANCE research had a DXA scan performed to evaluate BMD as part of the initial screening and recruitment approach. The ADVANCE research enrolled HIV-positive people and randomly assigned them to three ART arms. A total of 400 patients were reviewed. Of these 400 records reviewed, 62.3% were female. 80% of the participants were younger than 40 years old, and 3% were older than 50 years. 82% were virally suppressed with less than 50 viral copies. The prevalence of osteopenia was 25.5% and osteoporosis was 2.8%, observed in predominantly African female participants aged between 30 and 39 years. The findings of this study confirm that there is pre-existing bone loss among HIV-infected ART naïve individuals. Approximately 28.3% in our study had clinically confirmed evidence of bone loss and of these, 2.8% of the entire cohort had osteoporosis. Bone loss was most prevalent in black females who are virologically suppressed

Distal radius fractures are the most common osteoporotic fractures among women. The treatment of these fractures has been shifting from a traditional non-operative approach to surgery, using volar locking plate (VLP) technology. Surgery, however, is not without risk, complications including failure to restore an anatomic reduction, fracture re-displacement, and tendon rupture. The VLP implant is also marked by bone loss due to stress-shielding related to its high stiffness relative to adjacent bone. Recently, a novel internal, composite-based implant, with a stiffness less than the VLP, was designed to eradicate the shortcomings associated with the VLP implant. It is unclear, however, what effect this less-stiff implant will have upon adjacent bone density distributions long-term. The objective of this study was to evaluate the long-term effects of the two implants (the novel surgical implant and the gold-standard VLP) by using subject-specific finite element (FE) models integrated with an adaptive bone formation/resorption algorithm. Specimen: One fresh-frozen human forearm specimen (female, age = 84 years old) was imaged using CT and was used to create a subject-specific FE model of the radius. Finite element modeling: In order to simulate a clinically relevant (unstable) fracture of the distal radius, a wedge of bone was removed from the model, which was approximately 10 mm wide and centered 20 mm proximal to the tip of the radial styloid. Bone remodeling algorithm: A strain-energy density (SED) based bone remodeling theory was used to account for bone remodeling. With this approach, bone density decreased linearly when SED per bone density was less than 67.5 µJ/g and increased when it was more than 232.5 µJ/g. When it was in the lazy zone (67.5 to 232.5 µJ/g), no changes in density occurred. Boundary conditions: A 180 N quasi-static force representing the scaphoid, and a 120 N quasi-static force representing the lunate was applied to the radius. The midshaft of the radius was constrained. FE outcomes: To examine the effects of stress shielding associated with each implant, the long-term changes of bone density within proximal transverse cross-sections of radius were inspected. The regional density analysis focused on three transverse cross-sections. The transverse cross-sections were positioned proximal to the subchondral plate, and were distanced 50 (cross-section A), 57 (cross-section B), and 64 mm (cross-section C) from the subchondral endplate. For both implants in all three cross-sections, cortical bone was reserved completely at the volar side. On the dorsal side, the cortical bone was completely resorbed in the VLP model. In all cross-sections, the averaged resultant density was higher for the “novel implant”. The difference ranged from 33% (cross-section A) to 36% (cross-section C) in favor of the “novel implant”. On average, the density values of the novel implant were 34% higher in transverse cross-sections (A, B, and C). This study showed that the novel implant offered higher density distributions compared to the VLP, which suggests that the novel implant may be superior to the VLP in terms of avoiding stress shielding

Stimulation of the mechanosensitive ion channel, Piezo1 promotes bone anabolism and SNPs in the Piezo1 locus are associated with changes in fracture risk. Osteocytes function as critical regulators of bone homeostasis by sensing mechanical signals. The current study used a human, cell-based physiological, 3D in vitro model of bone to determine whether loading of osteocytes in vitro results in upregulation of the Piezo1 pathway. Human Y201 MSCs, embedded in type I collagen gels and differentiated to osteocytes for 7-days, were subjected to pathophysiological load (5000 µstrain, 10Hz, 5 mins; n=6) with unloaded cells as controls (n=4). RNA was extracted 1-hr post load and assessed by RNAseq analysis. To mimic mechanical load and activate Piezo1, cells were differentiated to osteocytes for 13 days and treated ± Yoda1 (5µM, 2- and 24-hs, n=4); vehicle treated cells served as controls (n=4). RNA was subjected to RT-qPCR and data normalised to the housekeeping gene, YWHAZ. Media was analysed for IL6 release by ELISA. Mechanical load upregulated Piezo1 gene expression (16.5-fold, p<0.001) and expression of the transcription factor NFATc1, and matricellular protein CYR61, known regulators of Piezo1 mechanotransduction (3-fold; p= 5.0E-5 and 6.8-fold; p= 6.0E-5, respectively). After 2-hrs, Yoda1 increased the expression of the early mechanical response gene, cFOS (11-fold; p=0.021), mean Piezo1 expression (2.3-fold) and IL-6 expression (103-fold, p<0.001). Yoda1 increased the release of IL6 protein after 24 hours (7.5-fold, p=0.001). This study confirms Piezo1 as an important mechanosensor in osteocytes. Piezo1 activation mediated an increase in IL6, a cytokine that drives inflammation and bone resorption providing a direct link between mechanical activation of Piezo1, bone remodeling and inflammation, which may contribute to mechanically induced joint degeneration in diseases such as osteoarthritis. Mechanistically, we hypothesize this may occur through promoting Ca2+ influx and activation of the NFATc1 signaling pathway

Osteoclasts (OCs) are multinucleated cells that play a pivotal role in skeletal development and bone remodeling. Abnormal activation of OCs contributes to the development of bone-related diseases, such as osteoporosis, bone metastasis and osteoarthritis. Restoring the normal function of OCs is crucial for bone homeostasis. Recently, RNA therapeutics emerged as a new field of research for osteoarticular diseases. The aim of this study is to use non-coding RNAs (ncRNAs) to molecularly engineer OCs and modulate their function. Specifically, we investigated the role of the microRNAs (namely miR-16) and long ncRNAs (namely DLEU1) in OCs differentiation and fusion. DLEU1/DLEU2 region, located at chromosome 13q14, also encodes miR-15 and miR-16. Our results show that levels of these ncRNA transcripts are differently expressed at distinct stages of the OCs differentiation. Specifically, silencing of DLEU1 by small interfering RNAs (siDLEU1) and overexpression of miR-16 by synthetic miRNA mimics (miR-16-mimics) led to a significant reduction in the number of OCs formed per field (OC/field), both at day 5 and 9 of the differentiation stage. Importantly, time-lapse analysis, used to track OCs behavior, revealed a significant decrease in fusion events after transfection with siDLEU1 or miR-16-mimics and an alteration in the fusion mode and partners. Next, we investigated the migration profile of these OCs, and the results show that only miR-16-mimics-OCs, but not siDLEU-OCs, have a lower percentage of immobile cells and an increase in cells with mobile regime, compared with controls. No differences in cell shape were found. Moreover, mass-spectrometry quantitative proteomic analysis revealed independent effects of siDLEU1 and miR-16-mimics at the protein levels. Importantly, DLEU1 and miR-16 act by distinct processes and pathways. Collectively, our findings support the ncRNAs DLEU1 and miR-16 as therapeutic targets to modulate early stages of OCs differentiation and, consequently, to impair OC fusion, advancing ncRNA-therapeutics for bone-related diseases. Acknowledgements: Authors would like to thank to AO CMF / AO Foundation (AOCMFS-21-23A). SRM and MIA are supported by FCT (SFRH/BD/147229/2019 and BiotechHealth Program; CEECINST/00091/2018/CP1500/CT0011, respectively)

Aims. The aim of this retrospective study was to assess the incidence of early periprosthetic femoral fracture (PFF) associated with Charnley-Kerboull (CK) femoral components cemented according to the ‘French paradox’ principles through the Hueter anterior approach (HAA) in patients older than 70 years. Methods. From a prospectively collected database, all short CK femoral components implanted consecutively from January 2018 to May 2022 through the HAA in patients older than 70 years were included. Exclusion criteria were age below 70 years, use of cementless femoral component, and approaches other than the HAA. A total of 416 short CK prostheses used by 25 surgeons with various levels of experience were included. All patients had a minimum of one-year follow-up, with a mean of 2.6 years (SD 1.1). The mean age was 77.4 years (70 to 95) and the mean BMI was 25.3 kg/m. 2. (18.4 to 43). Femoral anatomy was classified according to Dorr. The measured parameters included canal flare index, morphological cortical index, canal-calcar ratio, ilium-ischial ratio, and anterior superior iliac spine to greater trochanter (GT) distance. Results. Among the 416 THAs, two PFFs (0.48% (95% confidence interval 0.13 to 1.74)) were observed, including one Vancouver type B2 fracture 24 days postoperatively and one intraoperative Vancouver type B1 fracture. Valgus malalignment and higher canal bone ratio were found to be associated with PFF. Conclusion. This study demonstrated that short CK femoral components cemented according to the French paradox were associated with a low rate of early PFF (0.48%) in patients aged over 70 years. Longer follow-up is warranted to further evaluate the rate of fracture that may occur during the bone remodelling process and with time. Cite this article: Bone Joint J 2024;106-B(3 Supple A):67–73

Abstract. OBJECTIVES. Bone health deterioration is a major public health issue. General guidelines for the limitation of bone loss prescribe a healthy lifestyle and a minimum level of physical activity. However, there is no specific recommendation regarding targeted activities that can effectively maintain lumbar spine bone health. To provide a better understanding of such influencing activities, a new predictive modelling framework was developed to study bone remodelling under various loading conditions. METHODS. The approach is based on a full-body subject-specific musculoskeletal model [1] combined with structural finite element models of the lumbar vertebrae. Using activities recorded with the subject, musculoskeletal simulations provide physiological loading conditions to the finite element models which simulate bone remodelling using a strain-driven optimisation algorithm [2]. With a combination of daily living activities representative of a healthy lifestyle including locomotion activities (walking, stair ascent and descent, sitting down and standing up) and spine-focused activities involving twisting and reaching, this modelling framework generates a healthy bone architecture in the lumbar vertebrae. The influence of spine-focused tasks was studied by adapting healthy vertebrae to an altered loading scenario where only locomotion activities were performed. RESULTS. The spine-focused activities were responsible for 57% of the overall bone mechanical stimulus of the five lumbar vertebrae. Cortical bone maintenance was more influenced by these activities in the superior vertebrae than in the inferior ones, with a stimulus degradation of 74% in L1 against 24% in L5 when adapted to the altered loading scenario. Trabecular bone stimulus degradation varied between 53% and 68%. CONCLUSION. The study suggests that locomotion activities are insufficient to maintain lumbar spine bone health. When appropriate, larger spine movements should be recommended as part of the minimum daily physical activities. Declaration of Interest. (b) declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported:I declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project

Several electrical fields are known to be present in bone tissue as originally described by Fukada and Yasuda in the year 1957. Intrinsic voltages can derive from bone deformation and reversely lead to mechanical modifications, called the piezoelectric effect. This effect is used in the clinic for the treatment of bone defects by applying electric and magnetic stimulation directly to the bone supplied with an implant such as the electroinductive screw system. Through this system a sinusoidal alternating voltage with a maximum of 700 mV can be applied which leads to an electric field of 5–70 V/m in the surrounding bone. This approach is established for bone healing therapies. Despite the established clinical application of electrical stimulation in bone, the fundamental processes acting during this stimulation are still poorly understood. A better understanding of the influence of electric fields on cells involved in bone formation is important to improve therapy and clinical success. To study the impact of electrical fields on bone cells in vitro, Ti6Al4V electrodes were designed according to the pattern of the ASNIS III s screw for a 6-well system. Osteoblasts were seeded on collagen coated coverslip and placed centred on the bottom of each well. During four weeks the cells were stimulated 3×45 min/d and metabolic and alkaline phosphatase (ALP) activity as well as gene expression of cells were analysed. Furthermore, supernatants were collected and proteins typical for bone remodelling were examined. The electrical stimulation did not exert a significant influence on the metabolic activity and the ALP production in cells over time using these settings. Gene expression of BSP and ALP was upregulated after the first 3 days whereas OPG was increased in the second half after 14 days of electrical stimulation. Moreover, the concentration of the released proteins OPG, IL-6, DKK-1 and OPN increased when cells were cultivated under electrical stimulation. However, no changes could be seen for essential markers, like RANKL, Leptin, BMP-2, IL-1beta and TNF-alpha. Therefore, further studies will be done with osteoblasts and osteoclasts to study bone remodelling processes under the influence of electrical fields more in detail. This study was supported by the German Research Foundation (DFG) JO 1483/1-1

Periprosthetic femoral fracture (PFF) following primary total hip arthroplasty (THA) is of raising concern with the aging of the population. The aim of this retrospective study was to assess the incidence of early PFF associated with Charnley- Kerboull (CK) stems cemented line-to-line according to the “French paradox” principles through the anterior approach (AA) in patients older than 70 years old. This monocentric study involved 25 surgeons with various level of experience. From a prospectively collected database, all CK stems (AmisK®, Medacta, Castel San Pietro, Switzerland) done consecutively from January 2018 to May 2022 through the AA in patients older than 70 years were included. The measured parameters included canal flare index (CFI), morphological cortical index (MCI), canal-calcar ratio (CCR), ilium-ischial ratio (IIR), ilium overhang, and anterior superior iliac spine (ASIS) to greater trochanter distance. Dorr classification was also recorded. A total of 416 CK stems performed by 25 surgeons were included. All patients had a minimal 3-month follow-up. The mean age was 77.4 years, and the mean BMI was 25.3 kg/m. 2. According to the Dorr classification 240 hips were of Dorr type A, 144 Dorr type B, and 2 Dorr type C. Mean CFI, MCI, CCR, IIR and ASIS-GT were 3.8, 0.5, 2.8, 2.5, and 101mm, respectively. Amongst the 416 THAs, one (0.24%; 95% CI 0.20 – 0.28%) early PFF Vancouver type B2 fracture that occurred 24 days postoperatively was observed. This study demonstrated that CK stems cemented according to the “French Paradox” were associated with an extremely low rate of early PFF in patients over 70 years. The observed results are better than those reported with uncemented or taper slip cemented stems. Longer follow-up is warranted to evaluate further rate of fracture that may occur during the bone remodeling process around the femoral component

Osteoarthritis (OA) is a common cause of chronic pain. Subchondral bone is highly innervated, and bone structural changes directly correlate with pain in OA. Mechanisms underlying skeletal–neural interactions are under-investigated. Bone derived axon guidance molecules are known to regulate bone remodelling. Such signals in the nervous system regulate neural plasticity, branching and neural inflammation. Perturbation of these signals during OA disease progression may disrupt sensory afferents activity, affecting tissue integrity, nociception, and proprioception. Osteocyte mechanical loading and IL-6 stimulation alters axon guidance signalling influencing innervation, proprioception, and nociception. Human Y201 MSC cells, embedded in 3D type I collagen gels (0.05 × 106 cell/gel) in 48 well plastic or silicone (load) plates, were differentiated to osteocytes for 7 days before stimulation with IL-6 (5ng/ml) with soluble IL-6 receptor (sIL-6r (40ng/ml) or unstimulated (n=5/group), or mechanically loaded (5000 μstrain, 10Hz, 3000 cycles) or not loaded (n=5/group). RNA extracted 1hr and 24hrs post load was quantified by RNAseq whole transcriptome analysis (NovaSeq S1 flow cell 2 × 100bp PE reads and differentially expressed neurotransmitters identified (>2-fold change in DEseq2 analysis on normalised count data with FDR p<0.05). After 24 hours, extracted IL-6 stimulated RNA was quantified by RT-qPCR for neurotrophic factors using 2–∆∆Ct method (efficiency=94-106%) normalised to reference gene GAPDH (stability = 1.12 REfinder). Normally distributed data with homogenous variances was analysed by two-tailed t test. All detected axonal guidance genes were regulated by mechanical load. Axonal guidance genes were both down-regulated (Netrin1 0.16-fold, p=0.001; Sema3A 0.4-fold, p<0.001; SEMA3C (0.4-fold, p<0.001), and up-regulated (SLIT2 2.3-fold, p<0.001; CXCL12 5-fold, p<0.001; SEMA3B 13-fold, p<0.001; SEMA4F 2-fold, p<0.001) by mechanical load. IL6 and IL6sR stimulation upregulated SEMA3A (7-fold, p=0.01), its receptor Plexin1 (3-fold, p=0.03). Neutrophins analysed in IL6 stimulated RNA did not show regulation. Here we show osteocytes regulate multiple factors which may influence innervation, nociception, and proprioception upon inflammatory or mechanical insult. Future studies will establish how these factors may combine and affect nerve activity during OA disease progression

Femoral shaft fractures are potentially devastating injuries. Despite this, clinical studies of the biomechanics of this injury are lacking. We aimed to clinically evaluate bone behaviour under high and low energy trauma in paediatric, adult and older patients. Single-centre retrospective study identifying all diaphyseal femoral fractures between Feb 2015-Feb 2017. Peri-prosthetic and pathological fractures were excluded. Patients were subdivided into groups 1 (paediatric, <16yo), 2 (adult, 17–55yo) and 3 (older, >55yo) to reflect immature, peak bone age and osteoporotic bone respectively. Chi-Squared analysis assessed significance of bone age to degree of comminution and fracture pattern. A p-value <0.05 was significant. A total 4130 radiographs were analysed with 206 femoral shaft fractures identified. Forty-three patients were excluded with 163 remaining. Group 1, 2 and 3 included 38, 37 and 88 patients respectively. Mean age 50.8 (SD 32.8) with male-to-female ratio of 1:1.2. Groups 1 and 3 included majority simple fractures (35/38 and 62/88 respectively). Group 2 included more comminuted injuries (33/37). Bone age to degree of comminution proved significant (p<0.05) with a bimodal distribution of simple fractures noted in groups 1 and 3. Energy to fracture was significant in group 2, where a high energy injury was associated with comminution (p<0.05). This study is the first to demonstrate an association between fracture comminution and age. Simple femoral shaft fractures showed a bimodal age distribution in paediatric and older patients regardless of mechanism energy. High energy mechanism trauma was directly related to fracture comminution at peak bone age

Bone remodelling is mediated through the synchronism of bone resorption (catabolism) by osteoclasts and bone formation (anabolism) by osteoblasts. Imbalances in the bone remodelling cycle represent an underling cause of metabolic bone diseases such as osteoporosis, where bone resorption exceeds formation (1). Current therapeutic strategies to repair osteoporotic bone fractures focus solely in targeting anabolism or supressing catabolism (2). However, these therapeutics do not reverse the structural damage present at the defect site, ultimately leading to impaired fracture healing, making the repair of osteoporotic fractures particularly challenging in orthopaedics. Herein, we focus on investigating a combined versatile pro-anabolic and anti-catabolic effect of Magnesium (Mg. 2+. ) to modulate bone cell behaviour (3), to develop an engineered biomimetic bio-instructive biomaterial scaffold structurally designed to enhance bone formation while impeding pathological osteoclast resorption activities to facilitate better bone healing and promote repair. Pre-osteoblasts MC3T3-E1 (OBs) and osteoclasts progenitors RAW 264.7 (OCs) cell lines were cultured in growth media exposed to increasing concentrations of MgCl. 2. (0, 0.5, 1, 10, 25 and 50mM) and the optimal concentration to concurrently promote the differentiation of OBs and inhibit the differentiation or funtion of RANKL-induced OCs was assessed. We next used Fluorescence Lifetime Imaging Microscopy to investigate changes in the metabolic pathways during OBs and OCs differentiation when exposed to increasing MgCl. 2. concentrations. We developed a range of magnesium-incorporated collagen scaffolds to permit the spatiotemporal release of Mg. 2+. within the established therapeutic window, and to investigate the behaviour of bone cells in a 3D environment. In our results, we reported an increase in the expression of the bone formation markers osteocalcin and osteopontin for OBs exposed to 10mM MgCl. 2. , and a significant downregulation of the osteoclast-specific markers TRAP and cathepsin K in RANKL-induced OCs differentiation when exposed to 25mM MgCl. 2. Moreover, 25mM MgCl. 2. induced changes in the energy metabolism of OCs from a predominantly oxidative phosphorylation towards a more glycolytic pathway suggesting a regulatory effect of Mg. 2+. in the underlying mechanisms of osteoclasts formation and function. The developed porous collagen-magnesium scaffolds significantly reduced the expression of early osteoclastogenic markers RANK and NFkB, and an elevated expression of the osteogenic markers Runx2 and Col1A1 was reported after 7 days. Our research to date has provided evidences to demonstrate the potential of Mg. 2+. to concurrently enhance osteogenesis while inhibiting osteoclastogenesis in vitro, potentially introducing new targets for developing therapies to repair osteoporotic bone fractures

Cigarette smoking has a negative impact on the skeletal system by reducing bone mass and increasing the risk of fractures through its direct or indirect effects on bone remodeling. Recent evidence shows that smoking causes an imbalance in bone turnover, making bone vulnerable to osteoporosis and fragility fractures. In addition, cigarette smoking is known to have deleterious effects on fracture healing, as a positive correlation has been shown between the daily number of cigarettes smoked and years of exposure to smoking, although the underlying mechanisms are not fully understood. Smoking is also known to cause several medical and surgical complications responsible for longer hospital stays and a consequent increase in resource consumption. Smoking cessation is, therefore, highly advisable to prevent the onset of metabolic bone disease. However, some of the consequences appear to continue for decades. Based on this evidence, the aim of our work was to assess the impact of smoking on the skeletal system, particularly bone fractures, and to identify the pathophysiological mechanisms responsible for the impairment of fracture healing. Because smoking represents a major public health problem, understanding the association between cigarette smoking and the occurrence of bone disease is necessary in order to identify potential new targets for intervention

Abstract. Objectives. Osteocytes function as critical regulators of bone homeostasis by sensing mechanical signals. Stimulation of the mechanosensitive ion channel, Piezo1 promotes bone anabolism and deletion of Piezo1 in osteoblasts and osteocytes decreases bone mass and bone strength in mice. This study determined whether loading of osteocytes in vitro results in upregulation of the Piezo1 pathway. Methods. Human MSC cells (Y201), embedded in type I collagen gels and differentiated to osteocytes in osteogenic media for 7-days, were subjected to pathophysiological load (5000 µstrain, 10Hz, 5 mins; n=6) with unloaded cells as controls (n=4). RNA was extracted 1-hr post load and Piezo1 activation assessed by RNAseq analysis (NovaSeq S1 flow cell 2 × 100bp PE reads). To mimic mechanical load and activate Piezo1, Y201s were differentiated to osteocytes in 3D gels for 13 days and treated, with Yoda1 (5µM, 2 hours, n=4); vehicle treated cells served as controls (n=4). Extracted RNA was subjected to RT-qPCR and data analysed by Minitab. Results. Low mRNA expression of PIEZO1 in unloaded cells was upregulated 5-fold following 1-hr of mechanical load (p=0.003). In addition, the transcription factor NFATc1, a known regulator of Piezo1 mechanotransduction, was also upregulated by load (2.4-fold; p=0.03). Y201 cells differentiated in gels expressed the osteocyte marker, SOST. Yoda1 upregulated PIEZO1 (1.7-fold; p=0.057), the early mechanical response gene, cFOS (4-fold; p=0.006), COL1A1 (3.9-fold; p=0.052), and IL-6 expression (7.7-fold; p=0.001). Discussion. This study reveals PIEZO1 as an important mechanosenser in osteocytes. Piezo 1 mediated increases in the bone matrix protein, type I collagen, and IL-6, a cytokine that drives inflammation and bone resorption. This provides a direct link between mechanical activation of Piezo 1, bone remodelling and inflammation, which may contribute to mechanically-induced joint degeneration in osteoarthritis. Mechanistically, we hypothesise this may occur through promoting Ca2+ influx and activation of the NFAT1 signalling pathway

Introduction and Objective. Global prevalence of obesity has risen almost three-fold between 1975 and 2016. Alongside the more well-known health implications of obesity such as cardiovascular disease, cancer and type II diabetes, is the effect of male obesity on testosterone depletion and hypogonadism. Hypogonadism is a well-known contributor to the acceleration of bone loss during aging, and obesity is the single biggest risk factor for testosterone deficiency in men. Understanding the micro and macro structural changes to bone in response to testosterone depletion in combination with a high fat ‘Western’ diet, will advance our understanding of the relationship between obesity and bone metabolism. This study investigated the impact of surgically induced testosterone depletion and subsequent testosterone treatment upon bone remodelling in mice fed a high fat diet. Materials and Methods. Male ApoE. −/−. mice were split into 3 groups at 7 weeks of age and fed a high fat diet: Sham surgery with placebo treatment, orchiectomy surgery with placebo treatment, and orchiectomy surgery with testosterone treatment. Surgeries were performed at 8 weeks of age, followed by fortnightly testosterone treatment via injection. Mice were sacrificed at 25 weeks of age. Tibiae were collected and scanned ex-vivo at 4.3μm on a SkyScan 1272 Micro-CT scanner (Bruker). Left tibiae were used for assessment of trabecular and cortical Volumes of Interest (VOIs) 0.2mm and 1.0mm respectively from the growth-plate bridge break. Tibiae were subsequently paraffin embedded and sectioned at 4μm prior to immunohistochemical evaluation of alkaline phosphatase. Results. Trabecular bone volume and mineral density were significantly reduced in orchiectomised mice compared to sham-operated controls; and these parameters were normalised to control levels in orchiectomised mice treated with testosterone. In contrast, Trabecular thickness was significantly higher in testosterone depleted animals. Cortical bone parameters and body weights did not significantly differ between groups. Levels of alkaline phosphatase did not differ significantly in cortical or trabecular osteoblasts between groups. Conclusions. Findings suggest that testosterone deficiency significantly reduces trabecular bone parameters, and testosterone therapy may be a useful intervention for the loss of bone mass in testosterone deficient males. These results indicate that testosterone therapy may be useful for the treatment of trabecular bone frailty in testosterone deficient males. Observed changes in trabecular bone do not appear to be due to decreased mineralisation caused by osteoblast alkaline phosphatase. Ongoing work includes histology analysis to elucidate the mechanisms underpinning the changes seen in the bones of testosterone deficient animals

Introduction:. Paley et al has developed a multiplier method for calculating both leg length and total height. In the development of this algorithm, they evaluated the effect of factors including bone age and sex. They established that sex had a significant impact, but adjusting for bone age did not improve accuracy. Bone age and menarche have been shown to improve other height prediction models. Purpose:. We used a large prospective cohort to evaluate if the multiplier is independent of physiological age using menarche as a proxy. Methods:. Using the ALSPAC dataset we determined the accuracy of the Paley multiplier for predicting total height and leg length, and assed weather if the date of first menses increased the accuracy of the multiplier. Female patients over the age of 8, with documented final height and final sub-ishial leg length over the age of 15 and a date of first menses were evaluated. Predicted final height was compared with actual final height at all data points. Results:. There were 28332 data points in 3062 girls prior to skeletal maturity in the total height cohort and 8395 data points in 2300 girls in the leg length cohort. When age was corrected using the difference in age at onset of menarche from average, the accuracy of multiplier decreased for both measurements. When a correction of 50% was used, there was an improvement in the accuracy of multiplier predictions, reducing the average error by up to 24%. Conclusions:. Previous studies have failed to demonstrate that the accuracy of the multiplier is improved when adjusted for bone age. We have used the date of first menses as a proxy for bone age and established that making a 50% correction for physiological age improves the accuracy of this method. Significance:. This will potentially allow more accurate prediction of leg length discrepancy, and total height in girls with early menarche

INTRODUCTION. The magnitude of principal strain is indicative of the risks of femoral fracture,. 1,2. while changes in femoral strain energy density (SED) after total hip arthroplasty (THA) have been associated with bone remodeling stimulus. 3. Although previous modeling studies have evaluated femoral strains in the intact and implanted femur under walking loads through successfully predicting physiological hip contact force and femoral muscle forces,. 1,2,3. strains during ‘high load’ activities of daily living have not typically been evaluated. Hence, the objective of this study was to compare femoral strain between the intact and the THA implanted femur under peak loads during simulated walking, stair descent, and stumbling. METHODS. CTs of three cadaveric specimens were used to develop finite element (FE) models of intact and implanted femurs. Implanted models included a commercially-available femoral stem (DePuy Synthes, Warsaw, IN, USA). Young's moduli of the composite bony materials were interpolated from Hounsfield units using a CT phantom and established relationships. 4. Peak hip contact force and femoral muscle forces during walking and stair descent were calculated using a lower extremity musculoskeletal model. 5. and applied to the femur FE models (Fig. 1). While maintaining the peak hip contact forces, muscle forces were further adjusted using an iterative optimization approach in FE models to reduce the femur deflection to the reported physiological range (< 5 mm). 2. Femoral muscle forces during stumbling were estimated utilizing the same optimization approach with literature-reported hip contact forces as input. 6. Maximum and minimum principal strains were calculated for each loading scenario. Changes in SED between intact and THA models were calculated in bony elements around the stem. RESULTS. As expected, high loads during stumbling resulted in the highest peak principal strains along femoral diaphysis (THA: 3179±523 and −4559±629 με; intact: 4232±818 and −5853±204 με) compared to stair descent and typically evaluated gait loads (THA: 1741±363 and −1893±76 με; intact: 2256±887 and −2509±493 με; Fig. 2). Principal strains in THA models peaked close to the tip of the femoral stem across three activities, compared with proximally located peak principal strains in the intact models (Fig. 2). Bony elements located medially and laterally to the femoral stem showed decreased SED after THA, while increased SED was observed in elements distal to the femoral stem (Fig. 3). DISCUSSION. Using appropriately distributed muscle forces, our model predicted similar peak principal strains and SED differences compared with reported values during walking (peak principal strains: ±1500 to ±2000 με. 1,2. ; SED differences: ± 0.02 MPa. 3. ). In addition to the close to failure level principal strains, stumbling showed the most noticeable changes in SED compared with the other two activities. Results suggest iterative bone remodeling simulations should include a composite of activities-of-daily-living loading conditions as well as appropriately distributed muscle forces. For any figures or tables, please contact authors directly

The advantages of unicompartmental knee arthroplasty (UKA) include its bone preserving nature, lower relative cost and superior functional results. Some temporary pain has been reported clinically following this procedure. Could this be related to bone remodeling? A validated bone remodeling algorithm may have the answers…. A 3D geometry of an intact human cadaveric tibia was generated using CT images. An all poly unicompartmental implant geometry was positioned in an inlay and onlay configuration on the tibia and the post-operative models created. An adaptive bone remodeling algorithm was used with finite element modeling to predict the bone remodeling behavior surrounding the implant in both scenarios. Virtual DEXA images were generated from the model and bone mineral density (BMD) was measured in regions of interest in the AP and ML planes. BMD results were compared to clinical results. The bone remodelling algorithm predicted BMD growth in the proximal anterior regions of the tibia, with an inward tendency for both inlay and onlay models. Looking in the AP plane, a maximum of up to 7% BMD growth was predicted and in the ML plane this was as high as 16%. Minimal BMD loss was observed, which suggests minimal disturbance to the natural bone growth following UKA. Positron emission tomography (PET) scans showed active hot spots in the antero- medial regions of the tibia. These results were consistent with the finite element modeling results. Bone remodeling behavior was found to be sensitive to sizing and positioning of the implant. The adaptive bone remodeling algorithm predicted minimal BMD loss and some BMD growth in the anterior region of the tibia following UKA. This is consistent with patient complaint and PET scans

We developed a 3D vascularized bone remodeling model embedding human osteoblast and osteoclast precursors and endothelial cells in a mineralized matrix. All the cells included in the model exerted their function, resulting in a vascularized system undergoing mineralized matrix remodeling. Bone remodeling is a dynamic process relying on the balance between the activity of osteoblasts and osteoclasts which are responsible for bone formation and resorption, respectively. This process is also characterized by a tight coupling between osteogenesis and angiogenesis, indicating the existence of a complex cross-talk between endothelial cells and bone cells. We have recently developed microscale in vitro hydrogel-based models, namely the 3D MiniTissue models, to obtain bone-mimicking microenvironments including a 3D microvascular network formed by endothelial cell self-assembly [1–2]. Here, we generated a vascularized 3D MiniTissue bone remodeling model through the coculture of primary human cells in a 3D collagen/fibrin (Col/Fib) matrix enriched with CaP nanoparticles (CaPn) to mimic bone mineralized matrix. Human umbilical vein endothelial cells (HUVECs), bone marrow mesenchymal stem cells (BMSCs), osteoblast (OBs) and osteoclast (OCs) precursors were cocultured in plain and CaPn-enriched Col/Fib according to the following experimental conditions: a) HUVECs-BMSCs; b) OBs-OCs; c) HUVECs-BMSCs-OBs-OCs. Undifferentiated BMSCs were used to support HUVECs in microvascular network formation. BMSCs and peripheral blood mononuclear cells were respectively pre-differentiated into OB and OC precursors through 7 days of culture in osteogenic or osteoclastogenic medium. Needle-shaped CaPn (Ø ∼20 nm, length ∼80 nm) were added to a collagen/fibrinogen solution. Cells were resuspended in a thrombin solution and then mixed with plain or CaPn-enriched collagen/fibrinogen. The cell-laden mix was injected in U-shaped PMMA masks and let to polymerize to generate constructs of 2×2×5 mm. 3. Samples were cultured for 10 days. Microvascular network formation was evaluated by confocal microscopy. OB differentiation was analyzed by quantification of Alkaline Phosphatase (ALP) and cell-mediated mineralization. OC differentiation was assessed by Tartrate-Resistant Acid Phosphatase (TRAP) and cell-mediated phosphate release quantification. HUVECs developed a robust 3D microvascular network and BMSCs differentiated into mural cells supporting vasculogenesis. The presence of CaPn enhanced OB and OC differentiation, as demonstrated by the significantly higher ALP and TRAP levels and by the superior cell-mediated mineralization and phosphate release measured in CaPn-enriched than in plain Col/Fib. The coculture of OBs and OCs with HUVECs and BMSCs further enhanced ALP and TRAP levels, indicating that the presence of HUVECs and BMSCs positively contributed to OB and OC differentiation. Remarkably, higher values of ALP and TRAP activity were measured in the tetraculture in CaPn-enriched Col/Fib compared to plain Col/Fib, indicating that also in the tetraculture the mineralized matrix stimulated OB and OC differentiation. The 3D MiniTissue bone remodeling model developed in this study is a promising platform to investigate bone cell and endothelial cell cross-talk. This system allows to minimize the use of cells and reagents and is characterized by a superior ease of use compared to other microscale systems, such as microfluidic models. Finally, it represents a suitable platform to test drugs for bone diseases and can be easily personalized with patient-derived cells further increasing its relevance as drug screening platform

Introduction and Objective. Curative resection of proximal humerus tumours is now possible in this era of limb salvage with endoprosthetic replacement considered as the preferred reconstructive option. However, it has also been linked with mechanical and non-mechanical failures such as stem fracture and aseptic loosening. One of the challenges is to ensure that implants will endure the mechanical strain under physiological loading conditions, especially crucial in long surviving patients. The objective is to investigate the effect of varying prosthesis length on the bone and implant stresses in a reconstructed humerus-prosthesis assembly after tumour resection using finite element (FE) modelling. Methods. Computed tomography (CT) scans of 10 humeri were processed in Mimics 17 to create three-dimensional (3D) cortical and cancellous solid bone models. Endoprostheses of different lengths manufactured by Stryker were modelled using Solidworks 2020. The FE models were divided into four groups namely group A consisting of the intact humerus and groups B, C and D composed of humerus-prosthesis assemblies with a body length of 40, 100 and 120 mm respectively and were meshed using linear 4-noded tetrahedral elements in 3matic 13. The models were then imported into Abaqus CAE 6.14. Isotropic linear elastic behaviour with an elastic modulus of 13400, 2000 and 208 000 MPa were assigned to the cortical bone, cancellous bone and prosthesis respectively and a Poisson's ratio of 0.3 was assumed for each material. To represent the lifting of heavy objects and twisting motion, a tensile load of 200 N for axial loading and a 5 Nm torsional load for torsional loading was applied separately to the elbow joint surface with the glenohumeral joint fixed and with all contact interfaces defined as fully bonded. A comparative analysis against literature was performed to validate the intact model. Statistical analysis of the peak von Mises stress values collected from predicted stress contour plots was performed using a one-way repeated measure of analysis of variance (with a Bonferroni post hoc test) using SPSS Statistics 26. The average change in stress of the resected models from the intact state were then determined. Results. The validation of the intact humerus displayed a good agreement with literature values. The peak bone stress occurred distally above the coronoid and olecranon fossa closer to the load application region in the intact and resected bone models with a significant amount of loading borne by the cortical bone, while the peak implant stress occurred at the bone-prosthesis contact interface under both loading conditions. Based on the results obtained, a statistically significant difference (p =.013) in implant stress was only seen to occur between groups B and C under tension. Results illustrate initiation of stress shielding with the bone bearing lesser stress with increasing resection length which may eventually lead to implant failure by causing bone resorption according to Wolff's law. The peak implant stress under torsion was 3–5 times the stress under tension. The best biomechanical behaviour was exhibited in Group D, having the least average change in stress from the intact model, 5% and 3.8% under tension and torsion respectively. It can be deduced that the shorter the prosthesis length, the more pronounced the effect on cortical bone remodelling. With the maximum bone and implant stresses obtained being less than their yield strength, it can be concluded that the bone-implant construct is safe from failure. Conclusions. The developed FE models verified the influence of varying the prosthesis length on the bone and implant stresses and predicted signs of stress shielding in longer endoprostheses. By allowing for 2 cm shortening in the upper extremity and post-surgical scarring, it is beneficial to err towards a shorter endoprosthesis

OA pathophysiology has a vascular component consisting of venous stasis resulting in intraosseous hypertension and hypoxia. In response, osteoblasts change their cytokine expression, accelerating bone remodelling and cartilage breakdown consistent with OA. We have characterized circulatory kinetics in OA bone in animal models with dynamic contrast enhanced MRI (DCE-MRI) and . 18. F PET and have demonstrated venous stasis and reduced perfusion that temporally precede and spatially coincide with OA lesions. Osteoblast uptake of . 18. F is consistent with abnormal perfusion, bone remodelling, and severity of OA. Circulatory kinetics with DCE-MRI in humans with OA of the knee exhibit similar venous outflow obstruction. Venous stasis is associated with hypoxia in subchondral bone. As an example of the effects of hypoxia on OA osteoblasts, we have described upregulation of fibrinolytic peptides, but a deficiency in the upregulation of PAI-1, leading to the generation of plasmin by human OA osteoblasts exposed to hypoxia in vitro. Plasmin is a serine protease that has been shown to degrade cartilage in OA. Abnormal circulatory kinetics by DCE-MRI may be an imaging biomarker of OA. Pharmacologic modulation of venous stasis would have a salutary effect on the physicochemical microcirculation of subchondral osteoblasts and the pathophysiology of OA

Introduction. A previous computational study on an all-polymer PEEK-on-UHMWPE total knee replacement implant showed improved periprosthetic bone loading, compared to a conventional implant [1]. That study used a simulated gait cycle to determine distal loading, but a patella was not included. Substantial distal decrease of bone remodeling stimulus was found, in accordance with previous reports [2], but it was not consistent with other clinical and post-mortem DEXA results, which found the largest loss of bone stock in the anterior region [3,4]. As patellofemoral forces are relatively low during gait compared to squatting, we simulated a deep squat, expecting that a high-demand activity would provide similar indications of bone loss as literature [3,4]. Consequently, we applied both high tibiofemoral and patellofemoral loads, to provide more insight in the potential benefits of a new PEEK-Optima® femoral component on periprosthetic bone stock. Methods. We adopted a deep squat finite element model from Zelle et al. and included quasi-static deep flexion and load sharing at the posterior condyles [6]. A new implant design was inserted, with three variations in material properties: intact, CoCr and PEEK. The stiffness of the femoral elements was mapped from CT and applied to either the cut femur only (CoCr and PEEK) or the entire femoral construct (intact). The strain energy density (SED) was evaluated in the periprosthetic region as a measure for bone remodeling stimulus. To examine the effects of the entire exercise, SED values were integrated over all increments. Results. During squat the highest SED values were found at the intercondylar region, behind the posterior condyles and behind the anterior flange, extending further inward to the bone. Both the lateral and medial view of the periprosthetic region show markedly different SED patterns from the conventional CoCr implant. Higher values originating proximally extended to lower values in the anterodistal region (Figure 1). However, in the CoCr reconstruction these anterodistal patterns less prominent or even absent. In Figure 2, simulated DEXA images are presented showing the bone remodeling stimulus throughout the periprosthetic volume. Overall, the image for CoCr shows darker areas than PEEK and the reference, further corroborating the findings shown in Figure 1. Moreover, it is visible that the PEEK reconstruction had SED values similar to the reference in the femoral component region. Discussion. This study has corroborated that the influence of the patella in high-demanding tasks is of great importance to the anterior periprosthetic bone stock [4,5]. The loss of bone remodeling stimulus in the CoCr reconstruction is in accordance with literature findings [2–4]. The resemblance of PEEK to the intact reference suggests that the new PEEK-Optima® femoral component could largely retain the integrity of the periprosthetic bone

INTRODUCTION. Total hip arthroplasty (THA) is a very successful orthopaedic treatment with 15 years implant survival reaching 95%, but decreasing age and increasing life expectancy of THA patients ask for much longer lasting solutions. Shorter and more flexible cementless stems are of high interest as these allow to maintain maximum bone stock and reduce adverse long-term bone remodeling.1 However, decreasing stem length and reducing implant stiffness might compromise the initial stability by excessively increasing interfacial stresses. In general, a good balance between implant stability and reduced stress shielding must be provided to obtain durable THA reconstruction.2. This finite element (FE) study aimed to evaluate primary stability and bone remodeling of a new design of short hip implant with solid and U-shaped cross-section. MATERIALS AND METHODS. The long tapered Quadra-H stem and the short SMS implants (Medacta International, Castel San Pietro, Switzerland) were compared in this study (Figure 1). A FE model of a femur was based on calibrated CT data of an 81 year-old male (osteopenic bone quality). Both titanium alloy implants were assigned an elastic modulus of 105 GPa and the Poisson's ratios were set to 0.3. Initial stability simulations included the hip joint force and all muscle loads during a full cycle of normal walking as calculated in AnyBody software (Anybody Technology AS, Denmark), whereas the remodeling simulation used the peak loads from normal walking and stair climbing activities. Initial stability results are presented as micromotions on the implant surface with a threshold of 40 µm.3 Bone remodeling outcomes are represented in a form of simulated Dual X-ray Absorptiometry (DEXA) scans and the quantitative bone mineral density (BMD) changes in 7 periprosthetic zones. RESULTS. The U-shaped SMS implant showed slightly higher micromotions (2.7% surface area exceeding 40 µm) than the Quadra-H stem (0.2%), whereas micromotions of solid SMS were considerably higher (8.4%) (Figure 2). The largest micromotions were found on medial side of all implants. The smallest bone loss one year post-operatively was predicted around the U-shaped SMS implant. Proximal zones (1, 6 and 7) showed the largest bone loss with average of 9.9%, 11.8% and 12.8% for the U-shaped SMS, solid SMS and Quadra-H respectively (Figure 3). The bone remodeling prediction for the Quadra-H stem was in good agreement with clinical DEXA measurements (overall bone loss of 5.5% vs. 5.7). CONCLUSION. The U-shaped SMS implant is clearly superior to its solid version and has potential to provide comparable initial stability as the long Quadra-H stem and considerably better long-term bone stock preservation

Nanotopographical cues on Ti surfaces have been shown to elicit different cell responses such as differentiation and selective growth. Bone remodelling is a continuous process requiring specific cues for optimal bone growth and implant fixation. In addition, the prevention of biofilm formation on surgical implants is a major challenge. We have identified nanopatterns on Ti surfaces that would be optimal for both bone remodelling and for reducing risk of bacterial infection. We used primary human osteoblast/osteoclast co-cultures and seeded them on flat Ti and three Ti nanosurfaces with increasing degrees of roughness, manufactured using anodisation under alkaline conditions (for 2, 2.5 and 3 hours). Cell growth and behaviour was assessed by scanning electron microscopy (SEM), immunofluorescence microscopy, histochemistry and quantitative RT-PCR methods. Bacterial growth on the nanowire surfaces was also assessed by confocal microscopy and SEM. From the three surfaces tested, the 2 h nanowire surface supported osteoblast and, to a lesser extent, osteoclast growth and differentiation. Bacterial viability was significantly reduced on the 2h surface. Hence the 2 h surface provided optimal bone remodelling conditions while reducing infection risk, making it a favourable candidate for future implant surfaces. This work was funded by EPSRC grant EP/K034898/1

Objectives. Many in vitro studies have investigated the mechanism by which mechanical signals are transduced into biological signals that regulate bone homeostasis via periodontal ligament fibroblasts during orthodontic treatment, but the results have not been systematically reviewed. This review aims to do this, considering the parameters of various in vitro mechanical loading approaches and their effects on osteogenic and osteoclastogenic properties of periodontal ligament fibroblasts. Methods. Specific keywords were used to search electronic databases (EMBASE, PubMed, and Web of Science) for English-language literature published between 1995 and 2017. Results. A total of 26 studies from the 555 articles obtained via the database search were ultimately included, and four main types of biomechanical approach were identified. Compressive force is characterized by static and continuous application, whereas tensile force is mainly cyclic. Only nine studies investigated the mechanisms by which periodontal ligament fibroblasts transduce mechanical stimulus. The studies provided evidence from in vitro mechanical loading regimens that periodontal ligament fibroblasts play a unique and dominant role in the regulation of bone remodelling during orthodontic tooth movement. Conclusion. Evidence from the reviewed studies described the characteristics of periodontal ligament fibroblasts exposed to mechanical force. This is expected to benefit subsequent research into periodontal ligament fibroblasts and to provide indirectly evidence-based insights regarding orthodontic treatment. Further studies should be performed to explore the effects of static tension on cytomechanical properties, better techniques for static compressive force loading, and deeper analysis of underlying regulatory systems. Cite this article: M. Li, C. Zhang, Y. Yang. Effects of mechanical forces on osteogenesis and osteoclastogenesis in human periodontal ligament fibroblasts: A systematic review of in vitro studies. Bone Joint Res 2019;8:19–31. DOI: 10.1302/2046-3758.81.BJR-2018-0060.R1

Background. Implant stability and is an important factor for adequate bone remodelling and both are crucial in the long-term clinical survival of total hip arthroplasty (THA). Assessment of early bone remodelling on X-rays during the first 2 years post-operatively is mandatory when stepwise introduction of a new implant is performed. Regardless of fixation type (cemented or cementless), early acetabular component migration is usually the weakest link in THA, eventually leading to loosening. Over the past years, a shift towards uncemented cup designs has occurred. Besides the established hydroxyapatite (HA) coated uncemented cups which provide ongrowth of bone, new uncemented implant designs stimulating ingrowth of bone have increased in popularity. These cups initiate ingrowth of bone into the implant by their open metallic structure with peripheral pores, to obtain a mechanical interlock with the surrounding bone, thereby stabilising the prosthesis in an early stage after implantation. This retrospective study assessed bone remodelling, osseointegration and occurrence of radiolucency around a new ingrowth philosophy acetabular implant. Methods. In a retrospectively, single centre cohort study all patients whom underwent primary THA with a Tritanium acetabular component in 2011 were included. Bone remodelling, osseointegration and occurrence of radiolucency were determined by two reviewers from X-ray images that were made at 6 weeks, 3–6-12 and 24 months post-operatively. Bone contact % was calculated based on the original Charnley and DeLee zones. According to Charnley and DeLee the outer surface of an acetabular cup is divided into 3 zones (1-2-3). For our analysis the original 3 zones were further divided into 2 producing 6 zones 1A to 3B. Each of these 6 zones were then further divided into 4 equal sections. We attributed 25 points per section in which complete bone contact without lucency was observed. If lucency was observed no points were attributed to the section. A fully osteointegrated cup in all 24 sections could therefore attain 600 points. The total of each section and zone was subsequently tallied and recalculated to produce the percentage of bone contact on a 1–100% score. Results. In 2011 131 patients; 54 male and 76 female with average age of 60.83 (SD 12.42) and 60.57 (SD 12.11) year respectively underwent primary THA at our institution and all where included in our study cohort. Majority of this cohort underwent primary THA due to osteoarthrosis and most patients were classified ASO I (18%) or ASA II (65%). At two year clinical follow-up two revision were performed. One constituted a femur and acetabulum revision due to leg length difference and a snapping hip phenomenon. Complications included 3 dislocations (all treated policlinic), 4 deep infections (all treated with Genta PMMA beads with prosthesis in situ and healed) and 1 removal of hematoma. In another patient the femoral component was revised due to a peri-prosthetic fracture. Mean bone contact % values for all Charnley and DeLee zones combined were calculated and improved from 68,18% (SD 22,36) at 6 weeks to 73,61% SD (16,26) at 3 months to 84,21% (SD 19,02) at 6 months to 86,90% (SD 16,0) at 1 year to 92,19% (SD 12,74) at two year follow-up. When analysing the bone contact % per individual zone a remarkable difference was found for zones 2A-B. In contrast to zone 1A-B and 3A-B the initial bone contact % was clearly although not significantly lower until two year follow-up. Conclusions. In this study, the bone apposition around Tritanium actebular component was retrospectively assessed until two year clinical. Our results show excellent bone apposition that continues to improve over time (at least until two year clinical follow-up) suggesting that the open trabecular Ti structure of the Tritanium has a positive effect on cup osseointegration. However, some recent reports have shown the development of reactive lines around cups with porous/trabecular metal surfaces, of which the meaning is still unclear. Our analysis indicated that especially acetabular zone 2A-B according to Charnley&DeLee needs time to establish a direct contact of the implant surface and the surrounding bone tissues. Perhaps this might be explained by reaming technique (underreaming vs line to line reaming) resulting in suboptimal seating of the cup. Therefore, careful follow-up of this new implant technology will remain necessary and continued in this study. We aim to improve cohort size and establish results at longer follow-up times. Furthermore we aim to correlate these results to RSA component migration analysis

Abstract. Objectives. Osteoporosis of the pelvis and femur is diagnosed in a high proportion of lower-limb amputees which carries an increased fracture risk and subsequently serious implications on mobility, physical dependency and morbidity. Through the development of biofidelic musculoskeletal and finite element (FE) models, we aim to determine the effect of lower-limb amputation on long-term bone remodelling in the hip and to understand the potential underpinning mechanisms for bone degradation in the younger amputee population. Methods. Our models are patient specific and anatomically accurate. Geometries are derived from MRI-scans of one bilateral, above-knee, amputee and one body-matched control subject. Musculoskeletal modelling enables comparison of muscle and joint reaction-forces throughout gait. This provides the loading scenario implemented in FE. FE modelling demonstrates the effect of loading on the amputated limb via a prosthetic socket by comparing bone mechanical stimulation in amputee and control cases. Results. Musculoskeletal modelling shows that the bilateral amputee has 25% higher peak hip-reaction force than controls but a 54% lower peak knee-reaction force. Compensation for missing muscles and joints cause large-scale changes to the muscle loading patterns of the residual limb. FE analysis shows a 32% reduction in bone stimulation within the proximal femur and an 81% reduction in the distal femoral shaft when compared to the healthy control. A shielding effect from weight-bearing through a prosthetic socket was observed that may offset any increases in joint and muscle loading at the amputated hip. Conclusions. Bone loss in the young amputee population could be driven by unloading osteopenia where altered joint and muscle loads cause altered mechanical stimulus in the femur. Over many cycles of remodelling, a net bone loss occurs. Importantly, this suggests that the issue is preventable, or even reversible, with the implementation of targeted loading regimes or changes to the design of the prosthetic socket. Declaration of Interest. (b) declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported:I declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project

Abstract. Objectives. The mechanisms underlying abnormal joint mechanics are poorly understood despite it being a major risk factor for developing osteoarthritis. This study investigated the response of a 3D in vitro bone cell model to mechanical load. Methods. Human MSC cells (Y201) embedded in 3D type I collagen gels were differentiated in osteogenic media for 7-days in deformable, silicone plates. Gels were loaded once (5000 µstrain, 10Hz, 3000 cycles), RNA extracted 1-hr post load and assessed by RT-qPCR and RNAseq analysis (n=5/treatment). Cell shape and phenotype were assessed by immunocytochemistry and phalloidin staining. Data was analysed by Minitab. Results. RTqPCR revealed cells expressed markers of mature osteocytes (E11, sclerostin, DMP-1) and osteoprotegerin (OPG), alkaline phosphatase and type I collagen (COL1A1). Immunolocalisation of sclerostin and DMP-1 protein along with phalloidin staining confirmed a dendritic osteocyte phenotype. Load almost abolished sclerostin gene expression (p=0.05) and reduced E11 (2-fold p=0.03); COL1A1 was unchanged (p=0.349). Using DEseq2 analysis, of the 981 genes differentially regulated more than 2-fold at FDR p<0.05, 159 were downregulated and 821 upregulated by load. These were involved in processes important in bone biology including the inflammatory response (56 genes), ECM organisation (27), ageing (30), response to mechanical load (23), ER stress (34), regulation of ossification (26), bone morphogenesis (14), cartilage development (14), programmed cell death (161), and positive regulation of bone mineralisation (6). Discussion. Y201 cells were successfully differentiated to osteocytes. The osteocytes’ mechanical response revealed regulation of factors that contribute to bone remodelling and inflammation. Since the biological mechanisms underlying mechanically induced joint degeneration are unclear, there is a need for humanised, cell models to delineate molecular pathways activated by mechanical load. Such pathways may reveal the molecular basis for genetic predispositions to osteoarthritis and identify new therapeutic targets. Declaration of Interest. (b) declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported:I declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project

Our aim in this pilot study was to evaluate the fixation of, the bone remodelling around, and the clinical outcome after surgery of a new, uncemented, fully hydroxyapatite-coated, collared and tapered femoral component, designed specifically for elderly patients with a fracture of the femoral neck. We enrolled 50 patients, of at least 70 years of age, with an acute displaced fracture of the femoral neck in this prospective single-series study. They received a total hip replacement using the new component and were followed up regularly for two years. Fixation was evaluated by radiostereometric analysis and bone remodelling by dual-energy x-ray absorptiometry. Hip function and the health-related quality of life were assessed using the Harris hip score and the EuroQol-5D. Up to six weeks post-operatively there was a mean subsidence of 0.2 mm (−2.1 to +0.5) and a retroversion of a mean of 1.2° (−8.2° to +1.5°). No component migrated after three months. The patients had a continuous loss of peri-prosthetic bone which amounted to a mean of 16% (−49% to +10%) at two years. The mean Harris hip score was 82 (51 to 100) after two years. The two-year results from this pilot study indicate that this new, uncemented femoral component can be used for elderly patients with osteoporotic fractures of the femoral neck

The course of secondary fracture healing typically consists of four major phases including inflammation, soft and hard callus formation, and bone remodeling. Callus formation is promoted by mechanical stimulation, yet little is known about the healing tissue response to strain stimuli over shorter timeframes on hourly and daily basis. The aim of this study was to explore the hourly, daily and weekly variations in bone healing progression and to analyze the short-term response of the repair tissue to well-controlled mechanical stimulation. A system for continuous monitoring of fracture healing was designed for implantation in sheep tibia. The experimental model was adapted from Tufekci et al. 2018 and consisted of 3 mm transverse osteotomy and 30 mm bone defect resulting in an intermediate mobile bone fragment in the tibial shaft. Whereas the distal and proximal parts of the tibia were fixed with external fixator, the mobile fragment was connected to the proximal part via a second, active fixator. A linear actuator embedded in the active fixator moved the mobile fragment axially, thus stimulating mechanically the tissue in the osteotomy gap via well-controlled displacement being independent from the sheep's functional weightbearing. A load sensor was integrated in the active fixation to measure the force acting in the osteotomy gap. During each stimulation cycle the displacement and force magnitudes were recorded to determine in vivo fracture stiffness. Following approval of the local ethics committee, experiments were conducted on four skeletally mature sheep. Starting from the first day after surgery, the daily stimulation protocols consisted of 1000 loading events equally distributed over 12 hours from 9:00 to 21:00 resulting in a single loading event every 44 seconds. No stimulation was performed overnight. One animal had to be excluded due to inconsistencies in the load sensor data. The onset of tissue stiffening was detected around the eleventh day post-op. However, on a daily basis, the stiffness was not steadily increasing, but instead, an abrupt drop was observed in the beginning of the daily stimulations. Following this initial drop, the stiffness increased until the last stimulation cycle of the day. The continuous measurements enabled resolving the tissue response to strain stimuli over hours and days. The presented data contributes to the understanding of the influence of patient activity on daily variations in tissue stiffness and can serve to optimize rehabilitation protocols post fractures

Objectives. The exact aetiology and pathogenesis of microdamage-induced long bone fractures remain unknown. These fractures are likely to be the result of inadequate bone remodelling in response to damage. This study aims to identify an association of osteocyte apoptosis, the presence of osteocytic osteolysis, and any alterations in sclerostin expression with a fracture of the third metacarpal (Mc-III) bone of Thoroughbred racehorses. Methods. A total of 30 Mc-III bones were obtained; ten bones were fractured during racing, ten were from the contralateral limb, and ten were from control horses. Each Mc-III bone was divided into a fracture site, condyle, condylar groove, and sagittal ridge. Microcracks and diffuse microdamage were quantified. Apoptotic osteocytes were measured using TUNEL staining. Cathepsin K, matrix metalloproteinase-13 (MMP-13), HtrA1, and sclerostin expression were analyzed. Results. In the fracture group, microdamage was elevated 38.9% (. sd 2.6. ) compared with controls. There was no difference in the osteocyte number and the percentage of apoptotic cells between contralateral limb and unraced control; however, there were significantly fewer apoptotic cells in fractured samples (p < 0.02). Immunohistochemistry showed that in deep zones of the fractured samples, sclerostin expression was significantly higher (p < 0.03) than the total number of osteocytes. No increase in cathepsin K, MMP-13, or HtrA1 was present. Conclusion. There is increased microdamage in Mc-III bones that have fractured during racing. In this study, this is not associated with osteocyte apoptosis or osteocytic osteolysis. The finding of increased sclerostin in the region of the fracture suggests that this protein may be playing a key role in the regulation of bone microdamage during stress adaptation. Cite this article: N. Hopper, E. Singer, F. Henson. Increased sclerostin associated with stress fracture of the third metacarpal bone in the Thoroughbred racehorse. Bone Joint Res 2018;7:94–102. DOI: 10.1302/2046-3758.71.BJR-2016-0202.R4

It has been reported that there is an association between Perthes’ disease and poverty. We examined the demographic data of a group of 240 children (263 hips) who presented with Perthes’ disease in Greater Glasgow, where the mean deprivation scores are substantially greater than in the rest of Scotland, to see if this association applied and whether other clues to the aetiology of Perthes’ disease could be found. There were 197 boys and 43 girls; 39 (16.25%) had a family history of Perthes’ disease. Bone age in this series was heavily skewed towards the lower percentiles. The mean number of siblings was 1.9, with 31 (12.9%) being an only child. Maternal age at the birth of the first child showed no preponderance of older mothers. Maternal smoking during and after pregnancy was noted in 132 (55%), which compared with the 52% reported in the population of Greater Glasgow in general. Of the children in our series, 60 (25%) were in social class IV and V. However, this applies to more than half of the population of Greater Glasgow. There was no significant evidence of a preponderance of Perthes’ disease in the most deprived groups. The aetiology of Perthes’ disease is likely to be multifactorial and may include a genetic or deprivation influence resulting in delayed bone age

Osteoporosis is a mineral bone disease arising from the predominance of osteoclastic bone resorption. Bisphosphonates which inhibit osteoclasts are commonly used in osteoporosis treatment, but are not without severe adverse effects like osteonecrosis of the jaw. The mechanisms behind the development of such phenomena is not well understood. Bone homeostasis is achieved through an intimate cross-talk between osteoclasts and osteoblasts. Thus, it is important to visualise activities of these cells simultaneously in situ. Currently, there are means to visualise osteoclast shape and numbers with tartrate-resistant alkaline phosphatase (TRAP) staining but no practical and accurate methods to quantify osteoclast activity in situ. This investigation aims to establish the use of ELF97, a substrate of TRAP, to visualise and quantify osteoclast activity. This provides vital clues to mechanisms of various bone disorders. TRAP dephosphorylation of ELF97 results in a detectable fluorescent product at areas of osteoclast activity. Osteoclastic activity was initiated in zebrafish by inducing crush injuries in tail fin rays. Colocalisation of ELF97 fluorescence with osteoclast-specific DsRed in transgenic zebrafish, visualised under confocal microscopy, is used to further establish the specificity of ELF97 to sites of osteoclastic activity. Quantification is established by comparing fluorescence between wild type, osteoclast-deficient mutants and bisphosphonate-treated zebrafish. The utility of ELF97 will also be investigated in terms of the stability of the florescent product. The investigation revealed that ELF97 and DsRed fluorescence were found commonly at crush sites with osteoclastic activity. Wild type zebrafish had greater fluorescence compared to osteoclast-deficient (p<0.0001) and bisphosphonate-treated zebrafish (p<0.0001) after 7 and 14 days post-crush, revealing that fluorescence from ELF97 corresponds to expected osteoclastic activity. Fluorescence of tail fins treated with ELF97 did not diminish over a period of 21 days of storage, demonstrating its stability. ELF97 is thus a useful means to visualise osteoclast activity, potentially crucial in more advanced investigations to understand bone disorders. It could be used in combination with other cellular markers in whole biological samples to study and experimentally manipulate bone remodelling

Introduction. Trabecular Titanium is a biomaterial characterized by a regular three-dimensional hexagonal cell structure imitating trabecular bone morphology. Components are built via Electron Beam Melting technology in aone- step additive manufacturing process. This biomaterial combines the proven mechanical properties of Titanium with the elastic modulus provided by its cellular solid structure (Regis 2015 MRS Bulletin). Several in vitro studies reported promising outcomes on its osteoinductive and osteoconductive properties: Trabecular Titanium showed to significantly affect osteoblast attachment and proliferation while inhibiting osteoclastogenesis (Gastaldi 2010 J Biomed Mater Res A, Sollazzo 2011 ISRN Mater Sci); human adipose stem cells were able to adhere, proliferate and differentiate into an osteoblast-like phenotype in absence of osteogenic factors (Benazzo 2014 J Biomed Mater Res A). Furthermore, in vivo histological and histomorphometric analysis in a sheep model indicated that it provided bone in-growth in cancellous (+68%) and cortical bone (+87%) (Devine 2012 JBJS). A multicentre prospective study was performed to assess mid-term outcomes of acetabular cups in Trabecular Titanium after Total Hip Arthroplasty (THA). Methods. 89 patients (91 hips) underwent primary cementless THA. There were 46 (52%) men and 43 (48%) women, with a median (IQR) age and BMI of 67 (57–70) years and 26 (24–29) kg/m2, respectively. Diagnosis was mostly primary osteoarthritis in 80 (88%) cases. Radiographic and clinical evaluations (Harris Hip Score [HHS], SF-36) were performed preoperatively and at 7 days, 3, 6, 12, 24 and 60 months. Bone Mineral Density (BMD) was determined by dual-emission X-ray absorptiometry (DEXA) according to DeLee &Charnley 3 Regions of Interest (ROI) postoperatively at the same time-points using as baseline the measureat 1 week. Statistical analysis was carried out using Wilcoxon test. Results. Median (IQR) HHS and SF-36 improved significantly from 48 (39–61) and 49 (37–62) preoperatively to 99 (96–100) and 76 (60–85) at 60 mo. (p≤0.0001). Radiographic analysis showed evident signs of bone remodelling and biological fixation, with presence of superolateral and inferomedial bone buttress, and radial trabeculae in ROI I/II. All cups resulted radiographically stable without any radiolucent lines. The macro-porous structure of this biomaterial generates a high coefficient of friction (Marin 2012 Hip Int), promoting a firm mechanical interlocking at the implant-bone interface which could be already observed in the operating room. BMD initially declined from baseline at 7 days to 6 months. Then, BMD slightly increased or stabilized in all ROIs up to 24 months, while showing evidence of partial decline over time with increasing patient' age at 60 months, although without any clinical significance in terms of patients health status or implant stability. Statistical significant correlations in terms of bone remodeling were observed between groups of patients on the basis of gender and age (p≤0.05). No revision or implant failure was reported. Conclusions. All patients reported significant improvements in quality of life, pain relief and functional recovery. Radiographic evaluation confirmed good implant stability at 60 months. These outcomes corroborate the evidence reported on these cups by orthopaedic registries and literature (Perticarini 2015 BMC Musculoskelet Disord; Bistolfi 2014 Min Ortop)

Aims: Comparing periprosthetic bone remodeling in 5 stem designs and the effects of the bone remodeling on stem migration. Methods: Bone remodeling at the proximal femur in 89 cemented THA of 5 stem designs (Exeter,Sp2_aluminum,Sp2_CoCr,SHP,Spectron) were followed up at 1 week, 2 years, and 5 years postoperatively by measuring bone mineral density (BMD) in 7 Gruen zones using dual energy x-ray absorptiometer (DEXA). The migrations of the femoral stem measured by Radiostereometric Analysis (RSA) during the same time period were compared with the changes in BMD. Results: An 8% to 25% decrease in BMD at the proximal femur, especially at the medial cortex, was found 5 years after cemented THA. Exeter showed the most favourable bone remodeling, whereas the SHP and Sp2_CoCr stems showed the worst bone remodeling (with bone loss of 15–27%), and the bone loss in Sp2_aluminum and Spectron stems were between (8–13%). The majority of the bone loss occurred within 2 years without major progress thereafter. The rate of the bone loss was significantly related to the design of the stem as well as gender and body mass index (BMI). A significant relation between the rate of bone loss and the migration of the femoral stem could not be established by the current study. Conclusions: The stiffness of the stem as well as the concept of stem design significantly affected the bone remodeling at the proximal femur. However, the rate of bone loss seemingly did not affect the migration of the femoral stem in the current study

A resorbable, antibiotic-eluting bone void filler (AEBVF) was developed to address device-related infections. The AEBVF provides two functions: osteoconductive matrix for bone restoration, and local antibiotic delivery to treat device-related infections. In vitro evaluations of this AEBVF demonstrated antimicrobial activity to 7 weeks against Staphylococcus aureus (S. aureus).1 Subsequent rabbit studies demonstrated bactericidal capacity2 of the AEBVF against 105 CFU S. aureus and osteoconductivity.1 We hypothesized that the AEBVF would restore bone volume while eliminating 105 CFU S. aureus in a pilot sheep femoral condyle defect model. Four groups (n=2/group) were utilized to assess osteoconductivity (Group A-commercial ProOsteon & B-AEBVF) and antimicrobial activity (Group C-ProOsteon with 105 CFU S. aureus & D-AEBVF with 105 CFU S. aureus). AEBVF devices comprised degradable polymers (PCL, PEG, PLGA), ProOsteon (Biomet, USA), CaCl2, and tobramycin.3 Devices (1.5cc ProOsteon or 6 AEBVF croutons) were implanted into rectangular defects in the medial face of each sheep femoral condyle. Defects were evaluated using backscatter electron microscopy, mineral apposition rate (MAR) analysis, and light microscopy with Sanderson's Rapid Bone Stain (SRBS). All animals in Groups A, B, and D survived to the 12-week endpoint. In contrast, Group C animals were euthanized 11 days post-op. MAR and SRBS demonstrated comparable bone remodeling and defect restoration after 12 weeks in Groups A, B, and D. Notably, implant volumes of Groups A and D were greatly diminished (0.16±0.1%; 0.35%) after 12 weeks, compared to Group A (13.23±3.2%) and Time “0” (16.8%). These data show the AEBVF device's ability to: eliminate 105 CFU S. aureus, promote bone remodeling comparable to known bone void filler, and degrade at rates that do not interfere with bone remodeling

Aseptic loosening can be considered as a combination of both mechanical and biological failure scenarios. This study investigated the influence of including bone remodelling in the simulation of aseptic loosening of cemented hip prostheses. A combined strain and damage stimulated bone adaptation algorithm (Mulvihill et al., Proc. ESB Summer Workshop, p.114–115, 2007) was modified for use on an apparent tissue level. Constant rate resorption or deposition occurs if local strain falls outside a quiescent reference strain range. Furthermore, damage accumulates as a function of tensile stress. Resorption and simultaneous repair is activated above a critical damage level. Model parameters are related to specific surface area expressed as a function of apparent tissue density. Elastic modulus was also a function of accumulated damage. This algorithm was applied in conjunction with a bone cement and cement-metal interfacial damage accumulation algorithm to simulate aseptic loosening for a retrospective dataset of early revision and long-term-unrevised patients (Lennon et al. JOR, 779-88, 2007). One year of walking activity was simulated and resultant migrations of the prostheses were used to indicate revision risk. The current implementation demonstrated increased migration for simulations with bone remodelling (p= 0.01). Variability was increased but mean predicted migration for early revisions was significantly higher than for the unrevised group (p= 0.03). Bulk bone remodelling was predicted primarily in the proximal regions. Interfacial bone remodelling demonstrated oscillation in damage at the interface due to alternate resorption-repair and deposition cycles. Interfacial bone density changes were more prominent in proximal regions but some models did show small amounts of resorption in more distal Gruen zones. We conclude that bone remodelling has potential to predict more realistic migration patterns but further development and assessment is needed to identify the correct parameters for the bone adaptation algorithm

Background. Stemless prostheses are recognized to be an effective solution for anatomic total shoulder arthroplasty (TSA) while providing bone preservation and shortest operating time. Reverse shoulder arthroplasty (RSA) with stemless has not showed the same effectiveness, as clinical and biomechanical performances strongly depend on the design. The main concern is related to stability and bone response due to the changed biomechanical conditions; few studies have analyzed these effects in anatomic designs through Finite Element Analysis (FEA), however there is currently no study analyzing the reverse configuration. Additionally, most of the studies do not consider the effect of changing the neck-shaft angle (NSA) resection of the humerus nor the proper assignment of spatial bone properties to the bone models used in the simulations. The aim of this FEA study is to analyze bone response and primary stability of the SMR Stemless prosthesis in reverse with two different NSA cuts and two different reverse angled liners, in bone models with properties assigned using a quantitative computed tomography (QCT) methodology. Methods. Sixteen fresh-frozen cadaveric humeri were modelled using the QCT-based finite element methodology. The humeri were CT-scanned with a hydroxyapatite phantom to allow spatial bone properties assignment [Fig. 1]. Two implanted SMR stemless reverse configurations were considered for each humerus: a 150°-NSA cut with a 0° liner and a 135°-NSA cut with a 7° sloped liner [Fig. 2]. A 105° abduction loading condition was simulated on both the implanted reverse models and the intact (anatomic) humerus; load components were derived from previous dynamic biomechanical simulations on RSA implants for the implanted stemless models and from the OrthoLoad database for the intact humeri. The postoperative bone volume expected to resorb or remodel [Fig. 3a] in the implanted humeri were compared with their intact models in sixteen metaphyseal regions of interest (four 5-mm thick layers parallel to the resection and four anatomical quadrants) by means of a three-way repeated measures ANOVA followed by post hoc tests with Bonferroni correction. In order to evaluate primary stability, micromotions at the bone-Trabecular Titanium interface [Fig. 3b] were compared between the two configurations using a Wilcoxon matched-pairs signed-rank test. The significance level α was set to 0.05. Results. With the exception of the most proximal layer (0.0 – 5.0 mm), the 150°-NSA configuration showed overall a statistically significant lower bone volume expected to resorb (p = 0.011). In terms of bone remodelling, the 150°-NSA configuration had again a better response, but fewer statistically significant differences were found. Regarding micromotions, there was a median decrease (Mdn = 3.2 μm) for the 135°-NSA configuration (Mdn = 40.3 μm) with respect to the 150°-NSA configuration (Mdn = 43.5 μm) but this difference was non-significant (p = 0.464). Conclusions. For the analyzed SMR Stemless configurations, these results suggest a reduction in the risk of bone resorption when a 0° liner is implanted with the humerus cut at 150°. The used QCT-based methodology will allow further investigation, as this study was limited to one single design and load case. For any figures or tables, please contact the authors directly

Purpose: In uncemented total hip arthroplasty, stem design is one of the important factors influencing bone remodeling. The purpose of this study was to determine the differences in bone remodeling between metaphyseal and diaphyseal fit stems. Methods: Twenty-three patients undergoing total hip arthroplasty (28 hips) with metaphyseal fit stems were matched to 27 patients (32 hips) undergoing uncemented total hip arthroplasty with diaphyseal fit stems. Preoperative radiographs were assessed for canal fill, canal shape, and bone quality. Postoperative radiographs were assessed for frequency and time of appearance of peri-prosthetic bone remodeling including spot welds, cortical hypertrophy and pedestal formation. All patients were examined by a modified Harris Hip Score. Results: The proximal canal shape and bone quality were similar in both groups. There was no difference in the frequency of spot welds at 1 year and 2 years. Spot welds were mainly located in Gruen zone 1. Cortical hypertrophy was greater (p < 0.05) at 6 months, 1 year and 2 years with the metaphyseal fit stem. Cortical hypertrophy was found only in Gruen zones 3 and 5. Halo pedestal formation was greater (p < 0.05) at 6 months with the metaphyseal fit stem but not at 1 year and 2 years. Calcar rounding was observed in 25 hips (90.0%) with metaphyseal fit stems and twenty hips (62.5%) with diaphyseal fit stems. At the last follow-up, average HHS was similar (90.6 +/− 1.5 / 91.7 +/− 1.7; metaphyseal / diaphyseal fit stems). No patient developed aseptic loosening. Conclusions: This is the first study to determine differences in bone remodeling between a metaphyseal and a diaphyseal fixed stem in uncemented THA. After one year, the only significant difference between these two groups was cortical hypertrophy, which was greater in patients undergoing metaphyseal fit stem insertion. Both stem designs demonstrated bone remodeling with no differences in spot welds or pedestal formation. At two years, there was no functional difference between these two patient groups. To further elucidate the relation between radiographic and clinical results, longer term follow-up is required

Introduction. Stemless shoulder implants have recently gained increasing popularity. Advantages include an anatomic reconstruction of the humerus with preservation of bone stock for upcoming revisions. Several implant designs have been introduced over the last years. However, only few studies evaluated the impact of the varying designs on the load transfer and bone remodeling. The aim of this study was to compare the differences between two stemless shoulder implant designs using the micro finite element (µFE) method. Materials and Methods. Two cadaveric human humeri (low and high bone mineral density) were scanned with a resolution of 82µm by high resolution peripheral quantitative computer tomography (HR-pQCT). Images were processed to allow virtual implantation of two types of reverse-engineered stemless humeral implants (Implant 1: Eclipse, Arthrex, with fenestrated cage screw and Implant 2: Simpliciti, Tornier, with three fins). The resulting images were converted to µFE models consisting of up to 78 million hexahedral elements with isotropic elastic properties based on the literature. These models were subjected to two loading conditions (medial and along the central implant axis) and solved for internal stresses with a parallel solver (parFE, ETH Zurich) on a Linux Cluster. The bone tissue stresses were analysed according to four subregions (dividing plane: sagittal and frontal) at two depths starting from the bone-implant surface and the distal region ending distally from the tip of Implant 1 (proximal, distal). Results. Medial loads produced higher bone tissue stresses when loading was applied along the implant axis. This was more prominent in the lower density bone, causing more than 3 times higher stresses in the highest region for both implants. Bone tissue stresses were also shown to be higher in the low density specimen, especially in the distal zone. The maximum bone tissue stress ratio for low/high density bone reached 4.4 below Implant 1 and 2.2 below Implant 2, occurring both with a medially-directed load. For both implants, the highest bone tissue stresses were predicted in the distal region than in the proximal region, with larger distal-to-proximal stress ratios below Implant 1 than Implant 2 (3.8 and 1.7, respectively). Discussion. Our µFE analyses show that the implant anchorage design clearly influences load transfer to the periprosthetic bone. The long fenestrated cage screw of Implant 1 showed more direct distal stress transfer, which may lead to stress shielding in the proximal region, in a larger extent than Implant 2 which tends to distribute loads more evenly. Furthermore, periprosthetic bone quality appears to be an important factor for load transfer, causing dramatic changes due to different loading condition and implant geometry. These findings will help further improve anchorage design for stemless humeral heads in order to minimize bone remodeling and the long-term fixation of these implants

Osteoarthritis (OA) is a highly prevalent degenerative joint disorder characterized by joint pain and physical disability. Aberrant subchondral bone induces pathological changes and is a major source of pain in OA. In the subchondral bone, which is highly innervated, nerves have dual roles in pain sensation and bone homeostasis regulation. The interaction between peripheral nerves and target cells in the subchondral bone, and the interplay between the sensory and sympathetic nervous systems, allow peripheral nerves to regulate subchondral bone homeostasis. Alterations in peripheral innervation and local transmitters are closely related to changes in nociception and subchondral bone homeostasis, and affect the progression of OA. Recent literature has substantially expanded our understanding of the physiological and pathological distribution and function of specific subtypes of neurones in bone. This review summarizes the types and distribution of nerves detected in the tibial subchondral bone, their cellular and molecular interactions with bone cells that regulate subchondral bone homeostasis, and their role in OA pain. A comprehensive understanding and further investigation of the functions of peripheral innervation in the subchondral bone will help to develop novel therapeutic approaches to effectively prevent OA, and alleviate OA pain.

Cite this article: Bone Joint Res 2022;11(7):439–452.

Introduction. Both the RANK/RANKL system and the endocannabinoid system have roles in bone remodelling. Activation of CB1 receptors on sympathetic nerve terminals in trabecular bone modulates bone remodelling by attenuating adrenergic inhibition over bone formation. CB2 receptors are involved in the local control of bone cell differentiation and function. Osteoblastic CB2 receptor activation negatively regulates RANKL mRNA expression indicating an interaction between the two systems and that efficient bone remodelling requires a balance between these two systems. The aim of the study was to establish the presence of the different components of the endocannabinoid system and the RANK/RANKL signalling pathway in human bone and osteoclast culture. Methods. Levels of endocannabinoids (AEA, 2-AG) and their related compounds (OEA, PEA) in human trabecular bone, obtained from patients undergoing elective orthopaedic surgery, were measured using Liquid Chromatography Mass Spectrometry (LC-MS-MS). mRNA for the endocannabinoid synthetic and catabolic enzymes (NAPE-PLD, DAGLa, FAAH, MAGL), cannabinoid-activated receptors (CB1, CB2, PPARs, TRPV1), and RANK, RANKL and NFkB were determined using Taqman Real-Time PCR. Osteoclasts were differentiated from U-937 cells (Human leukaemic monocyte lymphoma cell line), following the sequential treatment using TPA (0.1μg/ml) followed by either TNF-a (3ng/ml) or calcitriol (10. −8. M), cultured for up to 30 days. Osteoclasts were identified by positive staining with tartrate resistant acid phosphatase (TRAP), multinucleation and the ability to form resorption pits on calcium phosphate coated discs. Taqman Real-Time PCR was performed to detect the expression of the osteoc!. last marker genes TRAP and cathepsin K, together with genes of the endocannabinoid and RANK/RANKL signalling pathways. Results. AEA (5.1±0.7pmol/g), 2-AG (527.0±78.6 pmol/g), PEA (122.2±5.1pmol/g) and OEA (122.8±4.3pmol/g) were present in human trabecular bone. All components of the endocannabinoid system and RANK/RANKL pathways were present at the mRNA level in human trabecular bone. TRAP positive, multinucleated, calcium phosphate resorbing osteoclasts were observed from day 8 to day 23 of culture. mRNA expression of the osteoclast specific markers TRAP and cathepsin K and components of the endocannabinoid and the RANK/RANKL systems (with the exception of CB1) were up-regulated with osteoclast maturation with highest levels of expression on day 14. Conclusion. The detection of both synthetic and catabolic enzymes of the endocannabinoids in human trabecular bone and osteoclast culture indicates local skeletal production and regulation of endocannabinoids. The co-expression of all components of the endocannabinoid and the RANK/RANKL systems in human trabecular bone and osteoclast culture suggest possible interactions between the 2 systems in maintaining balanced bone remodelling, which may impact upon bone resorption seen in many bone diseases

For amputated patients, direct attachment of upper leg prosthesis to the skeletal system by a percutaneous implant is an alternative solution to the traditional socket fixation. Currently available implants, the OPRA system (Integrum AB, Göteborg, Sweden) and the ISP Endo/Exo prosthesis (ESKA Implants AG, Lübeck, Germany) [1-2] allow overcoming common soft tissue problems of conventional socket fixation and provide better control of the prosthetic limb [3], higher mobility and comfort [2, 4]. However, restraining issues such as soft-tissue infections, peri-prosthetic bone fractures [3, 5–8] and considerable bone loss around the stem [9], which might lead to implant's loosening, are present. Finally, a long a residual limb is required for implant fitting. In order to overcome the limiting biomechanical issues of the current designs, a new concept of the direct intramedullary fixation was developed. The aim was to restore the natural load transfer in the femur and allow implantations in short femur remnants (Figure 1). We hypothesize that the new design will reduce the peri-prosthetic bone failure risk and adverse bone remodeling. Generic CT-based finite element models of an intact femoral bone and amputated bones implanted with 3 analyzed implants were created for the study. Models were loaded with two loading cases from a normal walking obtained from the experimental measurements with the OPRA device [10-11]. Periprosthetic bone failure risk was evaluated by considering the von Mises stress criterion [12-14]. Subsequently the strain adaptive bone remodeling theory was used to predict long-term changes in bone mineral density (BMD) around the implants. The bone mineral content (BMC) change was measured around implants and the results were visualized in the form of DXA scans. The OPRA and the ISP implants induced the high stress concentration in the proximal region decreasing in the distal direction to values below physiological levels as compared with the intact bone. The stresses around the new design were more uniformly distributed along the cortex and resembled better the intact case. Consequently, the bone failure risk was reduced as compared to the OPRA and the ISP implants. The adaptive bone remodeling simulations showed high bone resorption around distal parts of the OPRA and the ISP implants in the distal end of the femur (on average −75% ISP to −78% OPRA after 60 months). The bone remodeling simulation did not reveal any bone loss around the new design, but more bone densification was seen (Figure 2). In terms of total bone mineral content (BMC) the OPRA and the ISP implants induced only a short-term bone densification in contrast to the new design, which provoked a steady increase in the BMC over the whole analyzed period (Figure 3). In conclusion, we have seen that the new design offers much better bone maintenance and lower failure probability than the current osseointegrated trans-femoral prostheses. This positive outcome should encourage further developments of the presented concept, which in our opinion has a potential to considerably improve safety of the rehabilitation with the direct fixation implants and allow treatment of patients with short stumps

Aims

Large acetabular bone defects encountered in revision total hip arthroplasty (THA) are challenging to restore. Metal constructs for structural support are combined with bone graft materials for restoration. Autograft is restricted due to limited volume, and allogenic grafts have downsides including cost, availability, and operative processing. Bone graft substitutes (BGS) are an attractive alternative if they can demonstrate positive remodelling. One potential product is a biphasic injectable mixture (Cerament) that combines a fast-resorbing material (calcium sulphate) with the highly osteoconductive material hydroxyapatite. This study reviews the application of this biomaterial in large acetabular defects.

Purpose: Femoroacetabular impingement (FAI) is recognized as a pathomechanical process that leads to hip osteoarthritis (OA). Past research has been focused on treatments for FAI; however, few studies have been done to link FAI with the progression of OA. It is hypothesized that elevated mechanical stimuli could provoke bone remodeling in the subchondral bone and articulating surfaces due to cam FAI (aspherical head-neck deformity), which would accelerate the progression of OA. Using finite element analysis (FEA), the aim is to compare healthy hips to hips with cam FAI – investigating the mechanical stimuli effect of FAI towards OA. Method: Net joint reaction forces were obtained from joint kinematics, kinetics, and by inverse dynamics calculation for a dynamic squat motion of a control subject and a cam FAI patient (both males with comparable age, BMI, and femur lengths). CT scans were acquired from both subjects. Data slices were compiled using 3D-DOCTOR (Able Software Corp, MA) to form a 3D model with slice thickness calibrated at 1.25mm in the superior-inferior axis. ANSYS (ANSYS, PA) software was used for FEA. The femur models were given quadrilateral shell elements and modeled as linear elastic orthotropic materials. The ground reaction forces were applied to the femur models, simulating dynamic loads, using boundary conditions specific to hip loading. Von Mises stresses were determined to examine stress concentrations and adverse loading conditions. Strain energy distributions were determined to examine the effect of stimuli on the initiation and rate of bone remodeling. Results: At the maximum squat-depth, the FEA results demonstrated that the net forces acting on the FAI hip produced high mechanical stimuli regions around the head and neck. The highest stress concentration (590 MPa) was located at the anterosuperior head-neck junction, where cam FAI is most prominent. For the control hip, stresses were significantly lower (maximum of 151 MPa) and dissipated around the head. For both the FAI and the control hip, the maximum strain energy concentrations were seen at the superior portion of the head (4.725 kJ vs. 2.192 kJ for FAI vs. control hip respectively). Conclusion: The increase in mechanical stimuli can be due to the loading configurations as well as to the abnormal geometry of the cam deformity. Assuming that the strain energy density (SED) and its rate is linearly proportional to the rate of bone turnover, based on a recent semi-mechanistic bone remodeling theory, a higher rate of bone turnover is expected in the FAI than in a normal hip. Depending on the level and rate of SED, the rate of bone remodeling will vary in order to provide a new homeostatic configuration. The next-step analysis, examining the mechanical stimuli in the acetabulum and its cartilage, is currently in progress. This would provide useful information about the possible locations of OA initiation and establish a link between FAI with cartilage degeneration

In the past it has been widely accepted that bone remodelling of the proximal femur after cementless total hip replacement is a result of the altered mechanical environment. Usually, there is are distribution of the stresses in the bone, and subsequently bone mass, from the metaphysis to the proximal part of the diaphysis. The design rationale for some cementless stems is to transmit load to the proximal femur and thus to preserve the bone mineral content in this area. The aim of the present study was to investigate the relationship between postoperative strain shielding of the proximal femur and the bone remodelling after insertion of two different cementless femoral stems. Experimental study: Twelve pairs of human cadaveric femurs were instrumented with strain gauge rosettes in Gruen zones2 to 7 and the cortical strains were measured during simulation of one leg stance before and after insertion of a custom stem (Unique, SCP) or an anatomic stem (ABG, Stryker-Howmedica). Clinical study: In a prospective, randomized study including 80 patients, the same types of stems were inserted and the bone mineral density (BMD) was measured during the first two years postoperatively using DEXA. Then, the pattern of remodelling was compared with the gradient of strain shielding in each of the Gruen zones in the frontal plane. In Gruen zone 7 the relative cortical strain shielding was45% in the femurs with a custom stem and 87% in the femurs with an anatomic stem. In zone 6 the corresponding figures were 2% and 38%, in zone 5 0% and15% and in zone 3 0% and 20%. The DEXA measurements showed a decrease in BMD in zone 7 of 22% and 23% for the two stems, respectively. In the other zones the bone loss was smaller and there was no difference between the stems. In the proximal zones there was a highly significant difference in strain shielding between femurs receiving a customor an anatomic stem. However, there was no difference in the pattern of bone remodelling. The bone remodelling around these two stems does not seem to mirror the gradient of strain shielding

Interestingly, recent studies have shown promising outcomes in elderly. To the best of our knowledge there are no reports available assessing sequential bone remodelling around DCPD (dicalcium phosphate dehydrate) coated short metaphyseal loading stem using serial radiography. Hence we report the unique patterns of bone remodelling in patients 70 years and older and whether these patterns were different from those seen in younger patients. A total of 41 consecutive primary hip arthroplasties were performed in patients with averaged age of 78.3 years using short stem. The presence and patterns of radiolucent lines, radio-opaque lines, calcar rounding, proximal bone resorption, spot welds, cortical hypertrophy, and intramedullary bone formation around the distal tip were assessed at serial radiography up to averaged follow up of 24.5 months. In early stage of stability, the radio-opaque line appeared in lateral aspect of stem which might means the tension force of stem. On the contrary to this findings, the medial side of stem mainly showed the spot welds due to compression on calcar support. The sequential radiographic bone remodelling in 70 years and older showed the different pattern from those of 30 to 50 year-old. Formation of new endosteal trabeculation (spot welds) were seen only in 55.6% of stems among the elderly study group where as all patients showed spot welds in the younger group. Calcar resorption was often observed in younger group but the degree of calcar resorption was less. The other findings in elderly patients was not different compared to those of younger patients

Introduction: Periprosthetic bone resorption following total knee arthroplasty (TKA) is becoming a clinical concern. Decrease in bone quality jeapordises implant fixation, consequently leading to revision surgery. It has been suggested that a reduction in the local stress distribution may cause a decrease in bone mineral density (BMD). Computational bone remodelling has been used previously to predict bone adaptation in total hips. However, little has been reported on its use in TKA remodelling simulations. The aim of this study was to simulate the bone remodelling response of the femur and tibia following TKA, using an adaptive bone remodelling algorithm combined with the finite element (FE) method. Methods: 3D femur and tibia models were constructed from human cadaveric computed tomography images. Total knee implant geometries were used to reconstruct the knee joint.(RBK, Global Orthopaedic Technology, Australia). Both the femur and the tibia models were loaded at 45% gait cycle for normal walking gait using loads based on Taylor et al. A strain-adaptive remodelling algorithm was used to predict the remodelling behaviour of the femur and tibia following TKA. Analysis was performed using ABAQUS. Virtual DEXA images were generated from the FE models at predetermined time-points, BMD gain and loss were also assessed both quantitatively and qualitatively. Results: There was an increase and decrease in BMD for the femur and tibia models. BMD loss in the femur was predominantly experienced around the pegs and the distal femoral regions. Femoral BMD gain was displayed around the edges of the bone-implant interface, with higher activity at the anterior-medial and posterior-lateral aspects. BMD gain in the tibia was predominantly at the inferior end of the tibial tray’s keel, with the bone mass tending towards the medial aspect. Some bone gain was displayed on the medial side, surrounding the pegs and at the cortex. There was BMD loss on the lateral aspect of the tibia. Discussion: The adaptive bone remodelling algorithm has shown a good correlation with clinical findings. Reports of clinical and FE studies have shown that for cemented knees, most bone loss occurs at the distal femoral region, especially at the anterior aspect. It has been reported that in the tibia there is generally an over-all decrease in BMD in the proximal tibia and increase below the keel. This is in accordance with our predictions. BMD gain was found to be more predominant on the medial aspect. This may be due to the more medially inclined loading ratio, which affects the stress distribution within the bone. BMD gain in the tibia is shown to follow a path, which starts at the bottom of the keel and tends medially towards the tibial cortex. This illustrates the inherent tendency of load transfer to follow along the stiffest structural path

Aim. The aim of the study was to define the peculiarities of bone remodeling and identify specific parameters to development to heterotopic ossification. Materials and methods. Markers of bone formation (Osteocalcin, serum type 1 procollagen (N-terminal) (tP1NP)) and bone resorption (serum collagen type 1 cross-linked C-telopeptide (β-CTx)) were determined by the electrochemiluminiscence immunoassay “ECLIA” for Elecsys user cobas immunoassay analyser. In the study were included 23 patients with spinal cord injury – first group (average age 26.8 ± 3.9, duration of spinal cord injury from 3 to 12 months) and 23 healthy people's appropriate age and gender (average age 30.6 ± 6.0, years). In the first group included 11 patients with spinal cord injury with the presence of heterotopic ossification – subgroup I and 12 patients with spinal cord injury without heterotopic ossification – subgroup II. Results. The results of examination showed that patients of first group had significantly higher bone markers than control group: P1NP (256.7±48.2 ng/ml vs 49.3±5.1 ng/ml, p<0.001), serum β-CTx (1.47±0.23 ng/ml vs 0.45±0.04 ng/ml, p<0.0001), osteocalcin (52.2±9.8 ng/ml vs 24.9±2.08 ng/ml, p<0.001). There were obtained that levels of bone remodeling markers in patients with HO were significantly higher in comparison with patients without HO: P1NP (404.9±84.9 ng/ml vs 133.2±15.7 ng/ml, p<0.001), serum β-CTx (1.75±0.23 ng/ml vs 0.28±0.14 ng/ml, p<0.0001), osteocalcin (87.1±18.9 ng/ml vs 29.4±3.7 ng/ml, p<0.001). Conclusion. The bone formation and bone resorption markers in patient of first group were significantly higher than in healthy individuals of appropriate age. The rate of bone turnover markers in patient with HO was considerably higher than in patient without HO and the process of formation dominated over the resorption in patient with HO

Aims

The prevalence of scoliosis is not known in patients with idiopathic short stature, and the impact of treatment with recombinant human growth hormone on those with scoliosis remains controversial. We investigated the prevalence of scoliosis radiologically in children with idiopathic short stature, and the impact of treatment with growth hormone in a cross-sectional and retrospective cohort study.

Introduction and Aims: Although cortical hypertrophy (CH) in total hip arthroplasty (THA) has been associated with thigh pain and loose femoral stems, its presence has been variable in the literature, and it is an implant-specific phenomenon. The relationship of bony change to clinical outcome has not previously been examined in ceramic THA. Method: Hardened-bearing surfaces such as ceramics have the potential for altered patterns of force transmission into the femoral stem-bone interface, and as such could lead to altered bone remodelling. We investigate here the incidence and magnitude of CH at the Gruen zones, about the femoral stem of THA utilising ceramic-on-ceramic bearing surfaces without (n=36) or with (n=4) cement, and metal-polyethylene bearing surfaces without (n=40) or with (n=40) cement. Using multifactorial analysis, we examined the relationship of implant alignment, Harris and Oxford hip scores, and bone remodelling parameters. Results: In this study of 120 patients, the hip scores and x-rays are examined in the first year after total hip arthroplasty (THA), in order to evaluate bone remodelling in relation to clinical outcomes. Ceramics had the highest incidence (25%) and mean size (1.5 mm) of CH, followed by metal-polyethylene (17%, < 1 mm). No cemented implants exhibited CH. There was no significant relationship of bone remodelling to one-year hip scores, although there were significantly reduced pain scores in cases that exhibited endosteal remodelling at one year. CH in ceramic hips appears to be a mechanical phenomenon that is not associated with pain, varus drift, subsidence, or altered clinical outcome. Cement may buffer the stresses seen by the femur, and hence the stimulus for CH appears to be simply mechanical, and is increased with hardened-bearing surfaces. Conclusion: CH was more common in ceramic THA than metal-polyethylene, but was not associated with increased thigh pain or altered function. CH did not occur when cement was used, and as such we argue for a mechanical origin of the phenomenon, via altered load transmission into the femur through hardened-bearing surfaces

Introduction: Interest in the relationships between subchondral bone pathology and cartilage breakdown has been stimulated by the observations that bone marrow edema (BME) is related to both pain and bone remodeling and that the progression of cartilage lesions is greater in joints with significant BME. The hypothesis of this study is that changes in perfusion in subchondral bone bear a functional relationship to bone remodeling and cartilage degradation and are a part of a physicochemical signaling mechanism to osteoblasts. We have utilized dynamic, contrast-enhanced magnetic resonance imaging (MRI) to assess perfusion and BME in osteoarthritis (OA) and osteonecrosis (ON). Methods: Investigation of marrow perfusion in BME was performed in both the Dunkin-Hartley guinea pig model of OA patients and cohort of 26 control patients. The human study was performed on a 1.5T magnet using a dedicated surface coil and STIR [3500/17/150 (TR/TE/TI)] and VIBE [5.50/2.89 (TR/TE); 10° (flip angle)] pulse sequences. We determined pharmacokinetic parameters of marrow perfusion according to the two compartment model of Brix, which is characterized by rate and volume transfer constants that can be derived mathematically from time-signal intensity curves. Results: In the guinea pig model, inflow slope was similar at all ages; kel was decreased in the affected medial, but not in the normal lateral, tibia indicating reduced perfusion and outflow obstruction. Comparison of BME and perfusion metrics with morphological features (Mankin scores and subchondral bone plate thickness) at the medial tibia demonstrates that changes in perfusion dynamics precede bone remodeling and cartilage breakdown by several months. Compared to normal marrow, kinetic parameters of contrast-enhancement in areas of BME included higher initial slope (p< .001), higher A (p< .001), lower kep (p=.004), and lower kel (p< .001). In areas of BME around ON, there was significantly lower A (p=.009) and lower kel (p=.04) compared to BME adjacent to OA, but no significant difference in either initial slope (p=.06) or kep (p=.26). Discussion: To our knowledge, these are the first reports of the use of dynamic, enhanced-MRI to characterize bone marrow perfusion in BME associated with OA and ON. In the Dunkin-Hartley guinea pig, reduced perfusion in BME temporally precede alterations in bone remodeling and appearance of cartilage lesions, and are spatially localized to bone subjacent to eventual cartilage lesions. We have also demonstrated similar perfusion kinetics associated with BME in human ON and OA. Calculations of intraosseous pressure associated with outflow obstruction and decreased perfusion are consistent with measurements made in end-stage ON and OA. Osteoblasts are known to be responsive to flow, pressure, and pO2. Increased pressure and decreased flow associated with outflow obstruction may constitute physicochemical signals to osteoblasts which result in changes in cytokine expression and contribute to trabecular remodeling and cartilage breakdown

Osteoarthritis (OA) affects bone cartilage and underlying bone. Mechanically, the underlying bone provides support to the healthy growth of the overlying cartilage. However, with the progress of OA, bone losses and cysts occur in the bone and these would alter the biomechanical behaviour of the joint, and further leading to bone remodelling adversely affect the overlying cartilage. Human femoral head and femoral condyle were collected during hip or knee replacement operation due to the end stage of osteoarthritis (age 50–70), and the cartilage patches were graded and marked. A volunteer patient, with minor cartilage injury in his left knee while the right knee is intact, was used as control. Peripheral quantitative computed tomography (pQCT) was used to scan the bone and to determine the volumetric bone mineral density (vBMD) distribution. The examination of retrieved tissue explants from osteoarthritic patients revealed that patches of cartilage were worn away from the articular surface, and patches of intact cartilage were left. The cysts, ranging from 1 to 10mm were existed in all osteoarthritic bones, and were located close to cartilage defects in the weight-bearing regions, and closely associated with the grade of cartilage defect as measured by pQCT. The bone mineral density (vBMD) distribution demonstrated that the bones around cysts had much higher vBMD than the trabecular bone away from the cysts. Compared to the subchondral bone under thicker cartilage, subchondral bone within cartilage defect has higher vBMD. This may result from the mechanical stimulation as a result of bone-bone direct contact with less protection of cartilage in cartilage defect regions. This study showed an association between cartilage defect and subchondral bone mineral density distribution. Cysts were observed in all osteoarthritic samples and they are located close to cartilage defects in the weight-bearing regions. Cartilage defect altered the loading pattern of the joints, this leading to the bone remodelling and resultant bone structural changes as compared to the normal bone tissues. This work was financially supported by The ARUK Proof of Concept Award (grant no: 21160)

Biodegradable metals as orthopaedic implant materials receive substantial scientific and clinical interest. Marketed cardiovascular products confirm good biocompatibility of iron. Solid iron biodegrades slowly in vivo and has got supra-physiological mechanical properties as compared to bone and porous implants can be optimized for specific orthopaedic applications. We used Direct Metal Printing (DMP)3 to additively manufacture (AM) scaffolds of pure iron with fine-tuned bone-mimetic mechanical properties and improved degradation behavior to characterize their biocompatibility under static and dynamic 3D culture conditions using a spectrum of different cell types. Atomized iron powder was used to manufacture scaffolds with a repetitive diamond unit cell design on a ProX DMP 320 (Layerwise/3D Systems, Belgium). Mechanical characterization (Instron machine with a 10kN load cell, ISO 13314: 2011), degradation behavior under static and dynamic conditions (37ºC, 5% CO2 and 20% O2) for up of 28 days, with μCT as well as SEM/energy-dispersive X-ray spectroscopy (EDS) (SEM, JSM-IT100, JEOL) monitoring under in vivo-like conditions. Biocompatibility was comprehensively evaluated using a broader spectrum of human cells according to ISO 10993 guidelines, with topographically identical titanium (Ti-6Al-4V, Ti64) specimen as reference. Cytotoxicity was analyzed by two-way ANOVA and post-hoc Tukey's multiple comparisons test (α = 0.05). By μCT, as-built strut size (420 ± 4 μm) and porosity of 64% ± 0.2% were compared to design values (400 μm and 67%, respectively). After 28 days of biodegradation scaffolds showed a 3.1% weight reduction after cleaning, while pH-values of simulated body fluids (r-SBF) increased from 7.4 to 7.8. Mechanical properties of scaffolds (E = 1600–1800 MPa) were still within the range for trabecular bone, then. At all tested time points, close to 100% biocompatibility was shown with identically designed titanium (Ti64) controls (level 0 cytotoxicity). Iron scaffolds revealed a similar cytotoxicity with L929 cells throughout the study, but MG-63 or HUVEC cells revealed a reduced viability of 75% and 60%, respectively, already after 24h and a further decreased survival rate of 50% and 35% after 72h. Static and dynamic cultures revealed different and cell type-specific cytotoxicity profiles. Quantitative assays were confirmed by semi-quantitative cell staining in direct contact to iron and morphological differences were evident in comparison to Ti64 controls. This first report confirms that DMP allows accurate control of interconnectivity and topology of iron scaffold structures. While microstructure and chemical composition influence degradation behavior - so does topology and environmental in vitro conditions during degradation. While porous magnesium corrodes too fast to keep pace with bone remodeling rates, our porous and micro-structured design just holds tremendous potential to optimize the degradation speed of iron for application-specific orthopaedic implants. Surprisingly, the biological evaluation of pure iron scaffolds appears to largely depend on the culture model and cell type. Pure iron may not yet be an ideal surface for osteoblast- or endothelial-like cells in static cultures. We are currently studying appropriate coatings and in vivo-like dynamic culture systems to better predict in vivo biocompatibility

Osteoarthritis (OA) is a chronic degenerative joint disease characterized by progressive cartilage degradation, synovial membrane inflammation, osteophyte formation, and subchondral bone sclerosis. Pathological changes in cartilage and subchondral bone are the main processes in OA. In recent decades, many studies have demonstrated that activin-like kinase 3 (ALK3), a bone morphogenetic protein receptor, is essential for cartilage formation, osteogenesis, and postnatal skeletal development. Although the role of bone morphogenetic protein (BMP) signalling in articular cartilage and bone has been extensively studied, many new discoveries have been made in recent years around ALK3 targets in articular cartilage, subchondral bone, and the interaction between the two, broadening the original knowledge of the relationship between ALK3 and OA. In this review, we focus on the roles of ALK3 in OA, including cartilage and subchondral bone and related cells. It may be helpful to seek more efficient drugs or treatments for OA based on ALK3 signalling in future.

Background and aim. Despite good survivorship analysis for most uncemented tapered straight stems, new proposals modifying stem design in total hip replacement (THR) are being introduced in order to facilitate femoral revision surgery. We have evaluated the clinical and radiological results of four different designs of uncemented tapered straight stems implanted in our institution in order to assess: operative complications, clinical results, survivorship analysis for aseptic loosening and radiographic findings. Methods. 1008 hips implanted from 1998 to 2006 were prospectively followed for a mean of 12 years (range, 10 to 17). Four uncemented femoral designs employing a tapered straight stem were included: 209 Alloclassic stems, 420 Cerafit, 220 SL-Plus and 159 Summit. All hips had a 28 or 32 mm femoral head, and polyethylene (PE)-on metal or ceramic-on-ceramic bearing surface. Radiological femoral type, stem position, femoral canal filling at three levels and the possible appearance of loosening and other bone remodelling changes were recorded in all hips. Results. The rate of intra- and post-operative peri-prosthetic fractures ranged from 0 to 2.5%. No thigh pain was reported in unrevised patients. Among all groups, a total of 15 stems were revised for any cause. The revision rates for any cause at 12 years ranged from 97.1 to 99.3%. (p=0.1). 10 femoral components were revised for aseptic loosening: 6 Alloclassic stems with PE liner sterilized by Nitrogen and 3 SL-Plus stems with standard PE. No revision for aseptic loosening was found in the other designs. The survival rate for stem aseptic loosening was 97.1% (95% CI 95.6–100) for the Alloclassic group at 17 years and 98.2% (95% CI 96.2–100) for the SL-Plus at 14 years. The percentage with a neutral stem position was lower in the Alloclassic and SL-Plus groups (p=0.04). We found that femoral canal filling depended on stem group and stem position at three levels A, B and C (p<0.001). Femoral canal filling was greater in the SL-Plus group at three levels than the others (p<0.001). Bone remodelling changes were more frequent in the SL-Plus group, radiolucent lines (p<0.001) and cortical hypertrophy (p<0.001). Conclusion. Uncemented tapered straight stems consistently provide excellent clinical outcome and bone fixation. Newer proposals must consider these results, avoiding changing successful characteristics and concentrate on improving the less successful aspects

Aim of the study: Impaction bone grafting is examined and published by numerous authors in the literature, however possible correlation between bone remodeling at the site of revision hip arthroplasty and bone turnover markers is not well known yet. Materials and method: 22 patients undergoing revision hip arthroplasty with impaction bone grafting were enrolled in a prospective study. Bone turnover markers and bone mineral density (DXA) were measured preoperatively. WOMAC and Harris Hip Score (HHS) were evaluated pre- and postoperatively. During a one-year-period the same tests were performed after 6 weeks, 3 months, 6 months, 12 months respectively. The data were analyzed using logistic regression. Results: Significant bone remodeling was observed at the site of revision hip arthroplasty at the 6 month follow up. WOMAC and HHS improved significantly after surgery. One deep wound infection occurred due to MRSE, removal of the prosthesis was performed. Conclusion: Cancellous bone grafting secures primary stability for the hip implants, and after a period of 12 months proper bone remodeling is achieved

Long term, secondary implant fixation of Total Disc Replacements (TDR) can be enhanced by hydroxyapatite or similar osseo-conductive coatings. These coatings are routinely applied to metal substrates. The objective of this in vivo study was to investigate the early stability and subsequent bone response adjacent to an all polymer TDR implant over a period of six months in an animal model. Six skeletally mature male baboons (Papio annubis) were followed for a period of 6 months. Using a transperitoneal exposure, a custom-sized Cadisc L device was implanted into the disc space one level above the lumbo-sacral junction in all subjects. Radiographs of the lumbar spine were acquired prior to surgery, and post-operatively at intervals up to 6 months to assess implant stability. Flourochrome markers (which contain molecules that bind to mineralization fronts) were injected at specified intervals in order to investigate bone remodeling with time. Animals were humanely euthanized six months after index surgery. Test and control specimens were retrieved, fixed and subjected to histological processing to assess the bone-implant-bone interface. Fluorescence microscopy and confocal scanning laser microscopy were utilized with BioQuant image analysis to determine the bone mineral apposition rates and gross morphology. Radiographic evaluation revealed no loss of disc height at the operative level or adjacent levels. No evidence of subsidence or significant migration of the implant up to 6 months. Heterotopic ossification was observed to varying degrees at the operated level. Histology revealed the implant primary fixation features embedded within the adjacent vertebral endplates. Flourochrome distribution revealed active bone remodeling occurring adjacent to the polymeric end-plate with no evidence of adverse biological responses. Mineral apposition rates of between 0.7 and 1.7 microns / day are in keeping with literature values for hydroxyapatite coated implants in cancellous sites of various species. Radiographic assessment demonstrates that the Cadisc L implant remains stable in vivo with no evidence of subsidence or significant migration. Histological analysis suggests the primary fixation features are engaged, and in close apposition with the adjacent vertebral bone. Flourochrome markers provide evidence of a positive bone remodelling response in the presence of the implant