Surveillance of atypical femoral fractures in a nationwide fracture register.

Background and purpose - To continuously assess the incidence of atypical femoral fractures (AFFs) in the population is important, to allow the evaluation of the risks and benefits associated with osteoporosis treatment. Therefore, we investigated the possibility to use the Swedish Fracture Register (SFR) as a surveillance tool for AFFs in the population and to explore means of improvement. Patients and methods - All AFF registrations in the SFR from January 1, 2015 to December 31, 2018 were enrolled in the study. For these patients, radiographs were obtained and combined with radiographs from 176 patients with normal femoral fractures, to form the study cohort. All images were reviewed and classified into AFFs or normal femur fractures by 2 experts in the field (gold-standard classification) and 1 orthopedic resident educated on the specific radiographic features of AFF (educated-user classification). Furthermore, we estimated the incidence rate of AFFs in the population captured by the register through comparison with a previous cohort and calculated the positive predictive value (PPV) and, where possible, the inter-observer agreement (Cohen's kappa) between the different classifications. Results - Of the 178 available patients with AFF in the SFR, 104 patients were classified as AFF using the goldstandard classification, and 89 using the educated-user classification. The PPV increased from 0.58 in the SFR classification to 0.93 in the educated-user classification. The interobserver agreement between the gold-standard classification and the educated-user classification was 0.81. Interpretation - With a positive predictive value of 0.58 the Swedish Fracture Register outperforms radiology reports and reports to the Swedish Medical Products Agency on adverse drug reactions as a diagnostic tool to identify atypical femoral fractures.

Antiresorptive treatment and talar collapse after displaced fractures of the talar neck: a long-term follow-up of 19 patients.

Background and purpose - Displaced fractures of the talar neck are associated with a high risk of structural collapse. In this observational analysis we hypothesized that pharmacological inhibition of osteoclast function might reduce the risk of structural collapse through a reduction in bone resorption during revascularization of the injured bone.Patients and methods - Between 2002 and 2014 we treated 19 patients with displaced fractures of the talar neck with open reduction and internal fixation. Of these, 16 patients were available for final follow-up between January and November 2017 (median 12 years, IQR 7-13). Among these, 6 patients with Hawkins type 3 fractures and 2 patients with Hawkins type 2b fractures received postoperative antiresorptive treatment (7 alendronate, 1 denosumab) for 6 to 12 months. The remaining 8 patients received no antiresorptive treatment. The self-reported foot and ankle score (SEFAS) was available in all patients and 15 patients had undergone computed tomography (CT) at final follow-up, which allowed evaluation of structural collapse of the talar dome and signs of post-traumatic osteoarthritis.Results - The risk for partial collapse of the talar dome was equal in the 2 groups (3 in each group) and post-traumatic arthritis was observed in all patients. The SEFAS in patients with antiresorptive treatment was lower, at 21 points (95% CI 15-26), compared with those without treatment, 29 points (CI 22-35).Interpretation - Following a displaced fracture of the talar neck, we found no effect of antiresorptive therapy on the rate of talar collapse, post-traumatic osteoarthritis, and patient-reported outcomes.

Deep neural networks with promising diagnostic accuracy for the classification of atypical femoral fractures.

Background and purpose - A correct diagnosis is essential for the appropriate treatment of patients with atypical femoral fractures (AFFs). The diagnostic accuracy of radiographs with standard radiology reports is very poor. We derived a diagnostic algorithm that uses deep neural networks to enable clinicians to discriminate AFFs from normal femur fractures (NFFs) on conventional radiographs.Patients and methods - We entered 433 radiographs from 149 patients with complete AFF and 549 radiographs from 224 patients with NFF into a convolutional neural network (CNN) that acts as a core classifier in an automated pathway and a manual intervention pathway (manual improvement of image orientation). We tested several deep neural network structures (i.e., VGG19, InceptionV3, and ResNet) to identify the network with the highest diagnostic accuracy for distinguishing AFF from NFF. We applied a transfer learning technique and used 5-fold cross-validation and class activation mapping to evaluate the diagnostic accuracy.Results - In the automated pathway, ResNet50 had the highest diagnostic accuracy, with a mean of 91% (SD 1.3), as compared with 83% (SD 1.6) for VGG19, and 89% (SD 2.5) for InceptionV3. The corresponding accuracy levels for the intervention pathway were 94% (SD 2.0), 92% (2.7), and 93% (3.7), respectively. With regards to sensitivity and specificity, ResNet outperformed the other networks with a mean AUC (area under the curve) value of 0.94 (SD 0.01) and surpassed the accuracy of clinical diagnostics.Interpretation - Artificial intelligence systems show excellent diagnostic accuracies for the rare fracture type of AFF in an experimental setting.

Mechanical instability induces osteoclast differentiation independent of the presence of a fibrous tissue interface and osteocyte apoptosis in a rat model for aseptic loosening.

Background and purpose - Insufficient initial fixation or early micromotion of an implant is associated with a thin layer of fibrous tissue at the peri-implant interface. It is unknown if bone loss is induced by the fibrous tissue interface acting as an active biological membrane, or as a membrane that will produce supraphysiologic fluid flow conditions during gait, which activates the mechanosensitive osteocytes to mediate osteoclast differentiation. We investigated whether mechanically induced osteolysis is dependent on the fibrous tissue interface as a biologically active scaffold, or if it merely acts as a conduit for fluid flow, affecting the mechanosensitive osteocytes in the peri-prosthetic bone.Methods - Using a rat model of mechanically instability-induced aseptic loosening, we assessed whether the induction of osteoclast differentiation was dependent on the presence of a peri-implant fibrous interface. We analyzed the amount of osteoclast differentiation, osteocyte apoptosis, pro-resorptive cytokine expression and bone loss using immunohistochemistry, mRNA expression and micro-CT.Results - Osteoclast differentiation and bone loss were induced by mechanical instability but were not affected by the presence of the fibrous tissue membrane or associated with osteocyte apoptosis. There was no increased mRNA expression of any of the cytokines in the fibrous tissue membrane compared with the peri-implant bone.Interpretation - Our data show that the fibrous tissue membrane in the interface plays a minor role in inducing bone loss. This indicates that the peri-implant bone adjacent to loose bone implants might play an important role for osteoclast differentiation.

A Genome-Wide Association Study of Bisphosphonate-Associated Atypical Femoral Fracture.

Atypical femoral fracture is a well-documented adverse reaction to bisphosphonates. It is strongly related to duration of bisphosphonate use, and the risk declines rapidly after drug withdrawal. The mechanism behind bisphosphonate-associated atypical femoral fracture is unclear, but a genetic predisposition has been suggested. With the aim to identify common genetic variants that could be used for preemptive genetic testing, we performed a genome-wide association study. Cases were recruited mainly through reports of adverse drug reactions sent to the Swedish Medical Products Agency on a nation-wide basis. We compared atypical femoral fracture cases (n = 51) with population-based controls (n = 4891), and to reduce the possibility of confounding by indication, we also compared with bisphosphonate-treated controls without a current diagnosis of cancer (n = 324). The total number of single-nucleotide polymorphisms after imputation was 7,585,874. A genome-wide significance threshold of p < 5 × 10-8 was used to correct for multiple testing. In addition, we performed candidate gene analyses for a panel of 29 genes previously implicated in atypical femoral fractures (significance threshold of p < 5.7 × 10-6). Compared with population controls, bisphosphonate-associated atypical femoral fracture was associated with four isolated, uncommon single-nucleotide polymorphisms. When cases were compared with bisphosphonate-treated controls, no statistically significant genome-wide association remained. We conclude that the detected associations were either false positives or related to the underlying disease, i.e., treatment indication. Furthermore, there was no significant association with single-nucleotide polymorphisms in the 29 candidate genes. In conclusion, this study found no evidence of a common genetic predisposition for bisphosphonate-associated atypical femoral fracture. Further studies of larger sample size to identify possible weakly associated genetic traits, as well as whole exome or whole-genome sequencing studies to identify possible rare genetic variation conferring a risk are warranted.

Chronic anterior tibial stress fractures in athletes: No crack but intense remodeling.

PURPOSE: Delayed healing of anterior tibial stress fractures in athletes is related to high tensional forces acting across a putative fracture gap. These forces lead to crack propagation and create strains that exceed tissue differentiation thresholds for new bone to form in the gap. The "dreaded black line" is a radiographic hallmark sign of stress fractures considered to represent a transverse fracture gap. However, whether a fracture gap truly exists at the microscopic level remains unclear. The aim of this study was to describe the area of the "dreaded black line" microscopically and to identify signs of delayed healing. METHODS: Between 2011 and 2016, we included seven athletes with chronic anterior mid-shaft tibial stress fractures. The fracture site was excised as a cylindrical biopsy. The biopsy was evaluated with micro-CT and histology. The formation of new bone in the defect was evaluated radiographically. RESULTS: The "dreaded black line" seen on pre-operative radiographs in all patients could not be seen on the microscopic level. Instead, the area of the putative crack showed widened resorption cavities, lined with active osteoblasts, and surrounded by immature bone. This area of intense remodeling seemed to create a false impression of a fracture line on radiographs. Complete cortical continuity was restored at the biopsy site at median 8 months (range 6-13 months). CONCLUSION: Tibial stress fractures in athletes normally show no fracture defect, but a region of increased remodeling. The healing process is already ongoing but seems mechanically insufficient.

Low compartment pressure and myoglobin levels in tibial fractures with suspected acute compartment syndrome.

BACKGROUND: The intense ischemic pain of acute compartment syndrome can be difficult to discriminate from the pain related to an associated fracture. Lacking objective measures, the decision to perform fasciotomy is often only based on clinical findings and performed at a low threshold. Biomarkers of muscle cell damage might help to identify and monitor patients at risk. In patients with fractures, however, markers of muscle cell damage could be elevated because of other reasons associated with the trauma, which would make interpretation difficult. In a review of all patients who underwent emergency fasciotomy in our health care district we aimed to investigate the decision-making process and specifically the use of biomarkers in patients with and without fractures. METHODS: In the southeast health care region of Sweden 79 patients (60 men) with fractures (median age 26 years) and 42 patients (34 men) without associated fractures (median age 44 years) were treated with emergency fasciotomy of the lower leg between 2007 and 2016. Differences in clinical findings, p-myoglobin and p-creatine phosphokinase as well as pressure measurements were investigated. RESULTS: P-myoglobin was analyzed preoperatively in 20% of all cases and p-creatine phosphokinase in 8%. Preoperative levels of p-myoglobin were lower in patients with fractures (median 1065 µg/L, range 200-3700 µg/L) compared with those without fractures (median 7450 µg/L, range 29-31,000 µg/L), p < 0.05. Preoperative intracompartmental pressure was lower in the fracture group (median 45 mmHg, range 25-90 mmHg) compared with those without fractures (median 83 mmHg, range 18-130 mmHg), p < 0.05. CONCLUSIONS: Biomarkers are seldom used in the context of acute fasciotomy of the lower leg. Contrary to our expectations, preoperative levels of p-myoglobin and intracompartmental pressures were lower in fracture patients. These findings support differences in the underlying pathomechanism between the groups and indicate that biomarkers of muscle cell necrosis might play a more important role in the diagnosis of acute compartment syndrome than previously thought.

Marrow compartment contribution to cortical defect healing.

Background and purpose - Healing of shaft fractures is commonly described as regards external callus. We wanted to clarify the role of the bone marrow compartment in the healing of stable shaft fractures. Patients and methods - A longitudinal furrow was milled along the longitudinal axis of the femoral shaft in mice. The exposed bone marrow under the furrow was scooped out. The mice were then randomized to no further treatment, or to receiving 2 silicone plugs in the medullary canal distal and proximal to the defect. The plugs isolated the remaining marrow from contact with the defect. Results were studied with histology and flow cytometry. Results - Without silicone plugs, the marrow defect was filled with new bone marrow-like tissue by day 5, and new bone was seen already on day 10. The new bone was seen only at the level of the cortical injury, where it seemed to form simultaneously in the entire region of the removed cortex. The new bone seemed not to invade the marrow compartment, and there was a sharp edge between new bone and marrow. The regenerated marrow was similar to uninjured marrow, but contained considerably more cells. In the specimens with plugs, the marrow compartment was either filled with loose scar tissue, or empty, and there was only minimal bone formation, mainly located around the edges of the cortical injury. Interpretation - Marrow regeneration in the defect seemed to be a prerequisite for normal cortical healing. Shaft fracture treatment should perhaps pay more attention to the local bone marrow.

Lateral fixation: an alternative surgical approach in the prevention of complete atypical femoral fractures.

Little evidence is available on how to treat incomplete atypical fractures of the femur. When surgery is chosen, intramedullary nailing is the most common invasive technique. However, this approach is adopted from the treatment of other types of ordinary femoral fracture and does not aim to prevent the impending complete fracture by interrupting the mechanism underlying the pathology. We suggest a different surgical approach that intends to counteract the underlying biomechanical conditions leading to a complete atypical fracture and thus could be better suited in selected cases. Here, we share an alternative surgical approach and present two cases treated accordingly.

No Difference in Periprosthetic Bone Loss and Fixation Between a Standard-Length Stem and a Shorter Version in Cementless Total Hip Arthroplasty. A Randomized Controlled Trial.

BACKGROUND: Cementless femoral stems in total hip arthroplasty provide dependable clinical and radiographic results in the treatment of osteoarthritis. Stem length might affect the preservation of proximal bone stock and stability. We hypothesized that a shorter stem decreases proximal bone loss without affecting implant stability. METHODS: We randomly assigned 60 patients aged between 50 and 70 years to either a standard cementless femoral stem or a 35-mm shorter version. Patients were followed with dual-energy X-ray absorptiometry, radiostereometric analysis, Harris hip score, Western Ontario and McMaster Universities Osteoarthritis Index score, and clinical follow-up at 3, 6, 12, and 24 months. The trial is registered on ClinicalTrials.gov/. RESULTS: After 24 months, short stems had on average 3.8% (95% confidence interval, 1.2%-8.9%) more bone loss in zone 1 compared to standard stems (P = .14). In zone 7, the bone loss was on average 6.5% (95% confidence interval, 6.6%-19.7%) higher compared to standard stems (P = .33). After 24 months, standard stems had migrated 0.93 mm (range, 0.25-4.66 mm) and short stems 0.93 mm (range, 0.17-2.96 mm; Student t-test after log transformation, P = .3). Patient-reported outcome measures were similar in both groups. One patient in the standard stem group was diagnosed with infection, one with a posterior dislocation, and one with a deep venous thrombosis. No stems were revised. CONCLUSION: There were no statistically significant differences in periprosthetic bone loss or fixation between the stems at 24 months.

Risk of atypical femoral fracture during and after bisphosphonate use.

BACKGROUND AND PURPOSE: Use of bisphosphonates in women is associated with higher risk of atypical femoral fractures. The risk in terms of timing of use and type of bisphosphonate, and in men, remains unclear. PATIENTS AND METHODS: We reviewed radiographs of 5,342 Swedish women and men aged 55 years or more who had had a fracture of the femoral shaft in the 3-year period 2008-2010 (97% of those eligible), and found 172 patients with atypical fractures (93% of them women). We obtained data on medication and comorbidity. The risk of atypical fracture associated with bisphosphonate use was estimated in a nationwide cohort analysis. In addition, we performed a case-control analysis with comparison to 952 patients with ordinary shaft fractures. A short report of the findings has recently been presented (Schilcher et al. 2014a). Here we provide full details. RESULTS: The age-adjusted relative risk (RR) of atypical fracture associated with bisphosphonate use was 55 (95% CI: 39-79) in women and 54 (CI: 15-192) in men. In bisphosphonate users, women had a 3-fold higher risk than men (RR = 3.1, CI: 1.1-8.4). Alendronate users had higher risk than risedronate users (RR = 1.9, CI: 1.1-3.3). The RR after 4 years or more of use reached 126 (CI: 55-288), with a corresponding absolute risk of 11 (CI: 7-14) fractures per 10,000 person-years of use. The risk decreased by 70% per year since last use. INTERPRETATION: Women have a higher risk of atypical femoral fracture than men. The type of bisphosphonate used may affect risk estimates and the risk decreases rapidly after cessation.

Bisphosphonate use and atypical fractures of the femoral shaft.

BACKGROUND: Studies show conflicting results regarding the possible excess risk of atypical fractures of the femoral shaft associated with bisphosphonate use. METHODS: In Sweden, 12,777 women 55 years of age or older sustained a fracture of the femur in 2008. We reviewed radiographs of 1234 of the 1271 women who had a subtrochanteric or shaft fracture and identified 59 patients with atypical fractures. Data on medications and coexisting conditions were obtained from national registries. The relative and absolute risk of atypical fractures associated with bisphosphonate use was estimated by means of a nationwide cohort analysis. The 59 case patients were also compared with 263 control patients who had ordinary subtrochanteric or shaft fractures. RESULTS: The age-adjusted relative risk of atypical fracture was 47.3 (95% confidence interval [CI], 25.6 to 87.3) in the cohort analysis. The increase in absolute risk was 5 cases per 10,000 patient-years (95% CI, 4 to 7). A total of 78% of the case patients and 10% of the controls had received bisphosphonates, corresponding to a multivariable-adjusted odds ratio of 33.3 (95% CI, 14.3 to 77.8). The risk was independent of coexisting conditions and of concurrent use of other drugs with known effects on bone. The duration of use influenced the risk (odds ratio per 100 daily doses, 1.3; 95% CI, 1.1 to 1.6). After drug withdrawal, the risk diminished by 70% per year since the last use (odds ratio, 0.28; 95% CI, 0.21 to 0.38). CONCLUSIONS: These population-based nationwide analyses may be reassuring for patients who receive bisphosphonates. Although there was a high prevalence of current bisphosphonate use among patients with atypical fractures, the absolute risk was small. (Funded by the Swedish Research Council.).

Atypical femoral fractures, bisphosphonates, and mechanical stress.

Atypical fractures are stress fractures occurring in the femoral shaft and closely related to bisphosphonate use. We here discuss their radiographic definition and different putative etiologies, apart from mechanical stress. Long time reduction of skeletal remodeling because of bisphosphonate use is thought to allow time for the bone to deteriorate mechanically, resulting in reduced toughness. However, the risk of atypical fracture diminishes rapidly after cessation of treatment, which suggests more acute effects of bisphosphonate use. Microdamage normally accumulates at areas of high stress. Possibly, ongoing bisphosphonate use reduces the ability to resorb and replace areas of microdamage by targeted remodeling. This could lead to crack propagation beyond a point of no return, ending in macroscopic stress fracture.

Histology of 8 atypical femoral fractures: remodeling but no healing.

BACKGROUND AND PURPOSE: The pathophysiology behind bisphosphonate-associated atypical femoral fractures remains unclear. Histological findings at the fracture site itself may provide clues. PATIENTS AND METHODS: Between 2008 and 2013, we collected bone biopsies including the fracture line from 4 complete and 4 incomplete atypical femoral fractures. 7 female patients reported continuous bisphosphonate use for 10 years on average. 1 patient was a man who was not using bisphosphonates. Dual-energy X-ray absorptiometry of the hip and spine showed no osteoporosis in 6 cases. The bone biopsies were evaluated by micro-computed tomography, infrared spectroscopy, and qualitative histology. RESULTS: Incomplete fractures involved the whole cortical thickness and showed a continuous gap with a mean width of 180 µm. The gap contained amorphous material and was devoid of living cells. In contrast, the adjacent bone contained living cells, including active osteoclasts. The fracture surfaces sometimes consisted of woven bone, which may have formed in localized defects caused by surface fragmentation or resorption. INTERPRETATION: Atypical femoral fractures show signs of attempted healing at the fracture site. The narrow width of the fracture gap and its necrotic contents are compatible with the idea that micromotion prevents healing because it leads to strains within the fracture gap that preclude cell survival.

Fusion of electronic health records and radiographic images for a multimodal deep learning prediction model of atypical femur fractures.

Atypical femur fractures (AFF) represent a very rare type of fracture that can be difficult to discriminate radiologically from normal femur fractures (NFF). AFFs are associated with drugs that are administered to prevent osteoporosis-related fragility fractures, which are highly prevalent in the elderly population. Given that these fractures are rare and the radiologic changes are subtle currently only 7% of AFFs are correctly identified, which hinders adequate treatment for most patients with AFF. Deep learning models could be trained to classify automatically a fracture as AFF or NFF, thereby assisting radiologists in detecting these rare fractures. Historically, for this classification task, only imaging data have been used, using convolutional neural networks (CNN) or vision transformers applied to radiographs. However, to mimic situations in which all available data are used to arrive at a diagnosis, we adopted an approach of deep learning that is based on the integration of image data and tabular data (from electronic health records) for 159 patients with AFF and 914 patients with NFF. We hypothesized that the combinatorial data, compiled from all the radiology departments of 72 hospitals in Sweden and the Swedish National Patient Register, would improve classification accuracy, as compared to using only one modality. At the patient level, the area under the ROC curve (AUC) increased from 0.966 to 0.987 when using the integrated set of imaging data and seven pre-selected variables, as compared to only using imaging data. More importantly, the sensitivity increased from 0.796 to 0.903. We found a greater impact of data fusion when only a randomly selected subset of available images was used to make the image and tabular data more balanced for each patient. The AUC then increased from 0.949 to 0.984, and the sensitivity increased from 0.727 to 0.849. These AUC improvements are not large, mainly because of the already excellent performance of the CNN (AUC of 0.966) when only images are used. However, the improvement is clinically highly relevant considering the importance of accuracy in medical diagnostics. We expect an even greater effect when imaging data from a clinical workflow, comprising a more diverse set of diagnostic images, are used.

Dichotomous location of 160 atypical femoral fractures.

BACKGROUND AND PURPOSE: The risk of atypical fracture of the femur is associated with bisphosphonate use. While characterizing atypical fractures from a previous nationwide study in radiographic detail, we had the impression that the fractures were located either in the subtrochanteric region or in the shaft. We determined whether there is a dichotomy in this respect. PATIENTS AND METHODS: The distance between the atypical fractures and the lesser trochanter was measured on plain radiographs from 129 of 160 patients with atypical fractures, taken from 2008 through 2010. Analysis of the distances measured showed 2 clusters, which were then analyzed with regard to bisphosphonate use and age. RESULTS: The distribution of the distances would be best described as 2 clusters, with a dichotomy at 8 cm. The proximal (subtrochanteric) cluster comprised 25 patients who were generally younger (median 71 years) than the 104 patients in the cluster with shaft fractures (median 80 years). The 95% CI for the difference between medians was 4-11 years. Of the patients with subtrochanteric fractures, 18 of 25 used bisphosphonates as compared to 89 of 104 with shaft fractures. INTERPRETATION: The younger age and possibly smaller proportion of bisphosphonate users in the subtrochanteric cluster may be compatible with a greater influence of mechanical stress in the underlying pathophysiology of proximal fractures.

Autologous Bone Graft From the Ipsilateral Distal Femur in Tibial Condyle Fractures.

SUMMARY: Fractures of the proximal tibia often require void filling to support articular fragments in combination with internal fixation. The most common techniques are iliac autograft, allograft, or synthetic bone graft substitutes.The distal femur and its large volume condyles are a source of cancellous bone graft within the surgical site of an open reduction and internal fixation procedure. We have used a minimally invasive technique to harvest bone graft from the distal femur, using a bone graft drill. We performed this investigation to determine whether our technique of using distal femoral autograft to fill bone voids when treating proximal tibial fractures with open reduction and internal fixation is effective and safe. We also sought to determine the degree to which the bone graft incorporates into the tibia during fracture healing, the degree to which the harvest site heals, and the degree of secondary joint line depression.In all 12 patients, the bone graft had sufficient volume to fill the subchondral void in the proximal tibia, all fractures had healed at follow-up, and fracture reduction was maintained in most cases. We found no pain at the harvest site during follow-up, and there were no signs of drill penetration in articular or cortical structures. Drill holes at the harvest site showed sparse amounts of newly formed bone on CT in most of its circumference in all patients.There were no pathological changes in the femoral condyles with relation to the bone grafting procedure, and 5 patients showed radiographic signs of osteoarthritis in one or more joint compartments of the knee. The results showed this technique to provide similar success as reported alternatives without major complications and we continue to use this technique of harvesting distal femoral autograft to supplement open reduction and internal fixation of selected proximal tibial fractures.

Improved visualization of the bone-implant interface and osseointegration in ex vivo acetabular cup implants using photon-counting detector CT.

BACKGROUND: Successful osseointegration of joint replacement implants is required for long-term implant survival. Accurate assessment of osseointegration could enable clinical discrimination of failed implants from other sources of pain avoiding unnecessary surgeries. Photon-counting detector computed tomography (PCD-CT) provides improvements in image resolution compared to conventional energy-integrating detector CT (EID-CT), possibly allowing better visualization of bone-implant-interfaces and osseointegration. The aim of this study was to assess the quality of visualization of bone-implant-interfaces and osseointegration in acetabular cup implants, using PCD-CT compared with EID-CT. METHODS: Two acetabular implants (one cemented, one uncemented) retrieved during revision surgery were scanned using PCD-CT and EID-CT at equal radiation dose. Images were reconstructed using different reconstruction kernels and iterative strengths. Delineation of the bone-implant and bone-cement-interface as an indicator of osseointegration was scored subjectively for image quality by four radiologists on a Likert scale and assessed quantitatively. RESULTS: Delineation of bone-implant and bone-cement-interfaces was better with PCD-CT compared with EID-CT (p ≤ 0.030). The highest ratings were given for PCD-CT at sharper kernels for the cemented cup (PCD-CT, median 5, interquartile range 4.25-5.00 versus EID-CT, 3, 2.00-3.75, p < 0.001) and the uncemented cup (5, 4.00-5.00 versus 2, 2-2, respectively, p < 0.001). The bone-implant-interface was 35-42% sharper and the bone-cement-interface was 28-43% sharper with PCD-CT compared with EID-CT, depending on the reconstruction kernel. CONCLUSIONS: PCD-CT might enable a more accurate assessment of osseointegration of orthopedic joint replacement implants. KEY POINTS: • The bone-implant interface ex vivo showed superior visualization using photon-counting detector computed tomography (PCD-CT) compared to energy-integrating detector computed tomography. • Harder reconstruction kernels in PCD-CT provide sharper images with lower noise levels. • These improvements in imaging might make it possible to visualize osseointegration in vivo.

The release of osteoclast-stimulating factors on supraphysiological loading by osteoprogenitors coincides with expression of genes associated with inflammation and cytoskeletal arrangement.

Supraphysiological loading induced by unstable orthopedic implants initiates osteoclast formation, which results in bone degradation. We aimed to investigate which mechanosensitive cells in the peri-implant environment produce osteoclast-stimulating factors and how the production of these factors is stimulated by supraphysiological loading. The release of osteoclast-stimulating factors by different types of isolated bone marrow-derived hematopoietic and mesenchymal stem cells from six osteoarthritic patients was analyzed after one hour of supraphysiological loading (3.0 ± 0.2 Pa, 1 Hz) by adding their conditioned medium to osteoclast precursors. Monocytes produced factors that enhanced osteoclastogenesis by 1.6 ± 0.07-fold and mesenchymal stem cells by 1.4 ± 0.07-fold. Medium from osteoprogenitors and pre-osteoblasts enhanced osteoclastogenesis by 1.3 ± 0.09-fold and 1.4 ± 0.03-fold, respectively, where medium from four patients elicited a response and two did not. Next generation sequencing analysis of osteoprogenitors revealed that genes encoding for inflammation-related pathways and cytoskeletal rearrangements were regulated differently between responders and non-responders. Our data suggest that released osteoclast-stimulating soluble factors by progenitor cells in the bone marrow after supraphysiological loading may be related to cytoskeletal arrangement in an inflammatory environment. This connection could be relevant to better understand the aseptic loosening process of orthopedic implants.