Metastatic bone disease (MBD) is a significant contributor to diminished quality of life in cancer patients, often leading to pathologic fractures, hypercalcaemia, intractable bone pain, and reduced functional independence. Standard of care management for MBD patients undergoing orthopaedic surgery is multi-disciplinary, includes regular surgical follow-up, case by case assessment for use of bone protective medications, and post-operative radiation therapy to the operative site. The number of patients in southern Alberta receiving standard of care post-operative management is currently unclear. Our aim is to develop a database of all patients in southern Alberta undergoing orthopaedic surgery for MBD and to assess for deficiencies and opportunities to ensure standard of care for this complex patient population. Patients were identified for database inclusion by a search query of the Alberta Cancer Registry of all patients with a diagnosis of metastatic cancer who underwent surgery for an impending or pathologic fracture in the Calgary, South and Central Alberta Zones. Demographic information, primary cancer history, previous local and systemic treatments, anatomical location of MBD event(s), surgical fixation techniques, and post-operative care details were collected. The rate of standard of care post-operative treatment was evaluated. A comparison of outcomes between tertiary urban centres and rural centres was also completed. Survival was calculated from time of first operation to date of death. Univariate and multivariate analyses were performed to identify the impact of post-operative care variables on survival amongst patients surviving longer than one month. We identified 402 patients who have undergone surgical treatment for MBD in southern Alberta from 2006-2018. Median age at time of surgery was 66.3 years and 52.7% of patients were female. Breast, lung, prostate, renal cell and multiple myeloma were the most common primary malignancies (n=328, 81.6%). Median post-operative survival was 6.8 months (95%CI: 5.7-8.3). 203 patients (52.5%) were treated with post-operative radiotherapy and 159 patients (50.8%) had post-operative surgical follow-up. Only 39 patients (11.3%) received bone protective agents in the peri-operative period. On multivariate survival analysis, post-operative surgical follow-up was associated with improved survival (p<0.001). Patients were treated at nine hospitals across southern Alberta with most patients treated in an urban center (65.9%). Post-operative survival was significantly longer amongst patients treated in an urban center (9.0 months, 95%CI: 6.9-12.3 versus 4.3 months, 95%CI: 3.4-5.6, p<0.001). The burden of MBD is significant and increasing. With treatment occurring at multiple provincial sites, there is a need for standardized, primary disease-specific peri- and post-operative protocols to ensure quality and efficacious patient care. To provide evidence informed treatment recommendations, we have developed a database of all patients in southern Alberta undergoing orthopaedic surgery for MBD. Our results demonstrate that many patients were not treated according to post-operative standard of care recommendations. Notably, half of the included patients did not have documented surgical follow-up, post-operative radiation treatment was low and only 11% were actively treated with bone protective agents. This data justifies the need for established surgical MBD care pathways and provides reference data to benchmark prospective QA and QI outcomes in this patient population

Aim. The osteolytic process of osteomyelitis is, according to textbooks, caused by increased osteoclast activity due to RANKL production by osteoblasts. However, recent findings contradict this theory. Therefore, the aim was to investigate, in a porcine osteomyelitis model, how osteolysis is affected by massive inflammation and RANKL blocking, respectively. In parallel, patients with chronic osteomyelitis, diabetes, foot osteomyelitis, and fracture related infections (FRI) were included for advanced histological analysis of osteolysis. Methods. In pigs, a tibial implant cavity was created and inoculated with 10. 4. CFU of Staphylococcus aureus: Group A (n=7). Group B (n=7); + 1cm. 3. spongostan into the cavity. Group C (n=4); + systemic Denosumab treatment. Spongostan was used as an avascular material to support bacterial growth and thus increase the inflammatory response. Denosumab treatment was administrated to suppress osteoclast activity by RANKL inhibition (as in osteoporotic patients). The volume of osteolysis was accessed by CT scans. Immunohistochemistry with antibodies towards Cathepsin K was used to identify osteoclasts within the bone lesions. Briefly, the number of Cathepsin K positive cells, i.e., both precursors and bone resorbing osteoclasts, respectively, were counted in 10 high power fields (400x). In total, 50 bone infection patients were included (Herlev Hospital). From each patient five parried samples were taken for histology and microbiology, respectively. Histopathology, CT osteolysis volume estimation, and molecular expression of osteoclasts and inflammatory markers are ongoing. One FRI patient was osteoporotic and treated with Denosumab for 6 years. Results. All pigs were confirmed infected in the implant cavity. The volume (2.41 ± 1.29cm. 3. ) of osteolysis was significantly increased in the spongostan group in comparison to Group A (1.24 ± 0.59 cm. 3. ) (p=0.04). Thereby, the spongostan group had bacteria deeper into the bone from the inoculation point. Sufficient Denosumab treatment, i.e. reduced serum Ca was seen in 3 pigs. None of the Denosumab treated pigs showed reduced osteolysis in comparison to Group A (1.42 ± 0.63 cm. 3. ). The Cathepsin K score of Group C was 17 (15-23 IQR) of precursor osteoclasts and 2 (0-2 IQR) of osteoclasts in Howship lacunae. The Denosumab treated patient showed substantial osteolysis and histological analysis confirmed acute inflammatory. Conclusions. Application of spongostan, i.e., bacterial host optimization and massive inflammation promotes osteolysis and local bacterial dissemination. Osteoclast blocking with Denosumab showed no impact on osteolysis. Elucidation of the pathophysiology causing bone loss in osteomyelitis is fundamental. However, the widely accepted osteoclast-based theory might not be the only relevant

Surgical management for acute or impending pathologic fractures in metastatic bone disease (MBD) places patients at high-risk for post-operative venous thromboembolism (VTE). Due to the combination of malignancy, systemic cancer treatment, and surgical treatment, VTE-risk is increased 7-fold in patients with MBD compared to non-cancer patients undergoing the same procedure. The extent and duration of post-operative hypercoagulability in patients with MBD remains unknown and thromboprophylaxis guidelines were developed for non-cancer patients, limiting their applicability to address the elevated VTE-risk in cancer patients. Thrombelastography (TEG) analysis is a point-of-care test that measures clot formation, stabilization, and lysis in whole blood samples. The TEG parameter, maximal amplitude (MA), indicates clot strength and the threshold of ≥65 mm has been used to define hypercoagulability and predict VTE events in non-cancer patients requiring orthopaedic surgery. Therefore, this study aims to quantify the extent and duration of post-operative hypercoagulability in patients with MBD using serial TEG analysis. Consecutive adults (≥18 years) with MBD who required orthopaedic surgery for acute or impending pathologic fractures were enrolled into this single-centre, prospective cohort study. Serial TEG analysis was performed onsite using a TEG®6s haemostasis analyzer (Haemonetics Corporation, Boston, MA) on whole blood samples collected at seven timepoints: pre-operatively; on post-operative day (POD) 1, 3, and 5; and at 2-, 6-, and 12-weeks post-operatively. Hypercoagulability was defined as MA ≥65 mm. Participants received standardized thromboprophylaxis for four weeks and patient-reported compliance with thromboprophylaxis was recorded. VTE was defined as symptomatic DVT or PE, or asymptomatic proximal DVT, and all participants underwent a screening post-operative lower extremity Doppler ultrasound on POD3. Descriptive statistics were performed and difference between pre-operative MA values of participants with VTE versus no VTE was evaluated using Student's t-test (p≤0.05). Twenty-one participants (10 female; 47.6%) with a mean age of 70 ± 12 years were enrolled. Nine different primary cancers were identified amongst participants, with breast (23.8%), colorectal (19.0%), and lung cancer (14.3%) most frequently reported. Most participants (57.1%) were hypercoagulable pre-operatively, and nearly half remained hypercoagulable at 6- and 12-weeks post-operatively (47.1 and 46.7%, respectively). VTE occurred in 5 patients (23.8%) and mean MA was 68.1 ± 4.6 mm at the time of diagnosis. Mean pre-operative MA values were significantly higher (p=0.02) in patients who experienced VTE (68.9 ± 3.5 mm) compared to those who did not (62.7 ± 6.5 mm). VTE incidence was highest in the first week post-operatively, during which time four VTE events (80%) occurred. The proportion of patients in a hypercoagulable state increased at three consecutive timepoints, beginning on POD3 (85.0%), increasing on POD5 (87.5%), and peaking at 2-weeks post-operatively (88.9%). Current thromboprophylaxis guidelines do not consider cancer-associated risk factors that contribute to increased VTE incidence and prescription duration may be inadequate to address prolonged post-operative hypercoagulability in patients with MBD. The high rate of VTE events observed and sustained hypercoagulable state indicate that thromboprophylaxis may be prematurely terminated while patients remain at high risk for VTE. Therefore, extending thromboprophylaxis duration beyond 4-weeks post-operatively in patients with MBD warrants further investigation

Bone turnover and the accumulation of microdamage are impacted by the presence of skeletal metastases which can contribute to increased fracture risk. Treatments for metastatic disease may further impact bone quality. The present study aims to establish a preliminary understanding of microdamage accumulation and load to failure in osteolytic vertebrae following stereotactic body radiotherapy (SBRT), zoledronic acid (ZA), or docetaxel (DTX) treatment. Twenty-two six-week old athymic female rats (Hsd:RH-Foxn1rnu, Envigo, USA) were inoculated with HeLa cervical cancer cells through intracardiac injection (day 0). Institutional approval was obtained for this work and the ARRIVE guidelines were followed. Animals were randomly assigned to four groups: untreated (n=6), spine stereotactic body radiotherapy (SBRT) administered on day 14 (n=6), zoledronic acid (ZA) administered on day 7 (n=5), and docetaxel (DTX) administered on day 14 (n=5). Animals were euthanized on day 21. T13-L3 vertebral segments were collected immediately after sacrifice and stored in −20°C wrapped in saline soaked gauze until testing. µCT scans (µCT100, Scanco, Switzerland) of the T13-L3 segment confirmed tumour burden in all T13 and L2 vertebrae prior to testing. T13 was stained with BaSO. 4. to label microdamage. High resolution µCT scans were obtained (90kVp, 44uA, 4W, 4.9µm voxel size) to visualize stain location and volume. Segmentations of bone and BaSO. 4. were created using intensity thresholding at 3000HU (~736mgHA/cm. 3. ) and 10000HU (~2420mgHA/cm. 3. ), respectively. Non-specific BaSO. 4. was removed from the outer edge of the cortical shell by shrinking the segmentation by 105mm in 3D. Stain volume fraction was calculated as the ratio of BaSO. 4. volume to the sum of BaSO. 4. and bone volume. The L1-L3 motion segments were loaded under axial compression to failure using a µCT compatible loading device (Scanco) and force-displacement data was recorded. µCT scans were acquired unloaded, at 1500µm displacement and post-failure. Stereological analysis was performed on the L2 vertebrae in the unloaded µCT scans. Differences in mean stain volume fraction, mean load to failure, and mean bone volume/total volume (BV/TV) were compared between treatment groups using one-way ANOVAs. Pearson's correlation between stain volume fraction and load to failure by treatment was calculated using an adjusted load to failure divided by BV/TV. Stained damage fraction was significantly different between treatment groups (p=0.0029). Tukey post-hoc analysis showed untreated samples to have higher stain volume fraction (16.25±2.54%) than all treatment groups (p<0.05). The ZA group had the highest mean load to failure (195.60±84.49N), followed by untreated (142.33±53.08N), DTX (126.60±48.75N), and SBRT (95.50±44.96N), but differences did not reach significance (p=0.075). BV/TV was significantly higher in the ZA group (49.28±3.56%) compared to all others. The SBRT group had significantly lower BV/TV than the untreated group (p=0.018). Load divided by BV/TV was not significantly different between groups (p=0.24), but relative load to failure results were consistent (ZA>Untreated>DTX>SBRT). No correlations were found between stain volume fraction and load to failure. Focal and systemic cancer treatments effect microdamage accumulation and load to failure in osteolytic vertebrae. Current testing of healthy controls will help to further separate the effects of the tumour and cancer treatments on bone quality

Bone turnover and the accumulation of microdamage are impacted by the presence of skeletal metastases which can contribute to increased fracture risk. Treatments for metastatic disease may further impact bone quality. The present study aims to establish a preliminary understanding of microdamage accumulation and load to failure in osteolytic vertebrae following stereotactic body radiotherapy (SBRT), zoledronic acid (ZA), or docetaxel (DTX) treatment. Twenty-two six-week old athymic female rats (Hsd:RH-Foxn1rnu, Envigo, USA) were inoculated with HeLa cervical cancer cells through intracardiac injection (day 0). Institutional approval was obtained for this work and the ARRIVE guidelines were followed. Animals were randomly assigned to four groups: untreated (n=6), spine stereotactic body radiotherapy (SBRT) administered on day 14 (n=6), zoledronic acid (ZA) administered on day 7 (n=5), and docetaxel (DTX) administered on day 14 (n=5). Animals were euthanized on day 21. T13-L3 vertebral segments were collected immediately after sacrifice and stored in −20°C wrapped in saline soaked gauze until testing. µCT scans (µCT100, Scanco, Switzerland) of the T13-L3 segment confirmed tumour burden in all T13 and L2 vertebrae prior to testing. T13 was stained with BaSO. 4. to label microdamage. High resolution µCT scans were obtained (90kVp, 44uA, 4W, 4.9µm voxel size) to visualize stain location and volume. Segmentations of bone and BaSO. 4. were created using intensity thresholding at 3000HU (~736mgHA/cm. 3. ) and 10000HU (~2420mgHA/cm. 3. ), respectively. Non-specific BaSO. 4. was removed from the outer edge of the cortical shell by shrinking the segmentation by 105mm in 3D. Stain volume fraction was calculated as the ratio of BaSO. 4. volume to the sum of BaSO. 4. and bone volume. The L1-L3 motion segments were loaded under axial compression to failure using a µCT compatible loading device (Scanco) and force-displacement data was recorded. µCT scans were acquired unloaded, at 1500µm displacement and post-failure. Stereological analysis was performed on the L2 vertebrae in the unloaded µCT scans. Differences in mean stain volume fraction, mean load to failure, and mean bone volume/total volume (BV/TV) were compared between treatment groups using one-way ANOVAs. Pearson's correlation between stain volume fraction and load to failure by treatment was calculated using an adjusted load to failure divided by BV/TV. Stained damage fraction was significantly different between treatment groups (p=0.0029). Tukey post-hoc analysis showed untreated samples to have higher stain volume fraction (16.25±2.54%) than all treatment groups (p<0.05). The ZA group had the highest mean load to failure (195.60±84.49N), followed by untreated (142.33±53.08N), DTX (126.60±48.75N), and SBRT (95.50±44.96N), but differences did not reach significance (p=0.075). BV/TV was significantly higher in the ZA group (49.28±3.56%) compared to all others. The SBRT group had significantly lower BV/TV than the untreated group (p=0.018). Load divided by BV/TV was not significantly different between groups (p=0.24), but relative load to failure results were consistent (ZA>Untreated>DTX>SBRT). No correlations were found between stain volume fraction and load to failure. Focal and systemic cancer treatments effect microdamage accumulation and load to failure in osteolytic vertebrae. Current testing of healthy controls will help to further separate the effects of the tumour and cancer treatments on bone quality

Aim. Due to medical and organizational factors, it occurs in everyday practice that spacers are left in place longer than originally planned during a two-stage prosthesis exchange in the case of prosthetic joint infections. Patients are severely restricted in their mobility and, after initial antibiotic administration, the spacer itself only acts as a foreign body. The aim of this study is to analyze whether the duration of the spacer in situ has an influence on the long-term success of treatment and mortality. Method. We retrospectively studied all 204 two-stage prosthesis replacements of the hip and knee from 2012 to 2016 with a minimum follow-up of two years at an arthroplasty center with 3 main surgeons. The duration of the spacer interval was divided into two groups. Patients replanted within ten weeks (as is standard in multiple algorithms) after systemic antibiotic treatment were assigned to the ‘Regular Spacer Interval (< 70 days)’ group. If the spacer interval was longer, they were assigned to the ‘Long Spacer Interval (≥ 70 days)’ group. Results. Patients were on average 67.69 years old (SD 12.3). The mean duration of the spacer-interval was 100.9 days (range: 423.0; SD, 60.0). In 62 patients reimplantation could be performed within 70 days after explantation, in 142 patients this took longer (max. 438 days). In 26 patients, the spacer had to be changed at least once during this period (11 patients in the hip group, and 15 patients in the knee group). In the remaining cases, other medical or organizational reasons delayed replantation. Both groups were comparable concerning Charlson Comorbity Index, age, number of previous surgeries and laboratory infection markers. There was no statistically significant influence of the duration of the spacer interval on the infection free survival (n=204, p=0.32). There was also no influence on mortality (n=204, p=0.35) and aseptic implant failure (n=204, p=0.15). Conclusions. The timely replantation of a knee or hip prosthesis seems to be reasonable in general because the patients are strongly limited in their mobility and daily activities by the spacer. However, there does not seem to be a negative influence on infection eradication and survival due to a long spacer interval

Aim. Fungal orthopaedic infections most commonly affect people with complex surgical histories and existing comorbidities. Recurrence and re-infection rates are high, even with optimal surgical and systemic antifungal treatment. AmBisome liposomal amphotericin B has been suggested for local antifungal therapy, as an adjunctive treatment for fungal osteoarticular infections. Few case series have examined its clinical use when combined with polymethylmethacrylate cement PMMA), or with absorbable local antibiotic carriers. We aimed to evaluate the clinical use of local antifungal therapy with AmBisome liposomal amphotericin B (ABlaB), including tolerated doses, serious adverse events, and treatment outcomes. Method. A retrospective cohort of all patients treated with local antifungal therapy with ABlaB between January 2016 and January 2021 in a specialist orthopaedic hospital was identified using pharmacy records. Renal function, serious adverse events during treatment, surgical outcomes including spacer fracture and infection recurrence, were identified from electronic clinical records. The project was approved by the Institutional Review Board (clinical audit 6871). Results. 13 operations involving local antifungal therapy with ABlaB, in 12 patients, were identified. Eleven were infected with Candida species and one with Aspergillus. Mean follow-up was 22 months (range 4–46). Ten first stage arthroplasty revisions, 2 second stage arthroplasty revisions, and one debridement and removal of metalwork for fracture-related infection were performed. Locally implanted doses of ABlaB ranged from 100mg to 3600mg (50–400mg per 40g mix of PMMA). Six patients received ABlaB in absorbable antibiotic carriers containing calcium sulphate. This was noted to delay carrier setting. Patients were also given systemic antifungal therapy. No patients experienced serious adverse events related to toxicity from local antifungal therapy with ABlaB. There were no spacer fractures. Overall treatment success was 54% at final follow-up, although there were no recurrent fungal infections identified in patients experiencing treatment failure. Conclusions. Local antifungal therapy with liposomal amphotericin B, when combined with surgery and systemic therapy, appears to be a safe and well tolerated intervention in the management of complex fungal osteoarticular infections

Aims

Excision of chronic osteomyelitic bone creates a dead space which must be managed to avoid early recurrence of infection. Systemic antibiotics cannot penetrate this space in high concentrations, so local treatment has become an attractive adjunct to surgery. The aim of this study was to present the mid- to long-term results of local treatment with gentamicin in a bioabsorbable ceramic carrier.

Osteomyelitis is an infectious process in bone occasionally leading to bone destruction. Traditionally a two-stage operation is performed using PMMA + antibiotic beads or a spacer. In the second operation the void filler is removed and the defect is filled with autologous bone. Bioactive glass (BAG) S53P4 is an antibacterial biodegradable bone substitute. This feature is based on an increase in pH and the osmotic pressure around the BAG, a phenomenon which has been shown to kill both planktonic bacteria and bacteria in biofilm in-vitro. We analyzed retrospectively our early results of osteomyelitis patients treated with BAG from the patient's clinical history. The diagnosis was stated in addition to bacterial samples by MRI, CT and plain radiographs or by a combination of these. Between 2007–2013 we applied BAG as a void-filler in 20 cases (15 male and 5 female) of osteomyelitis in the lower (19) or the upper (1) limb in one-stage procedure. The patients had been suffering from symptoms of osteomyelitis a mean 3,5 months (0,25–24,00) and had a history of mean 3,5 (1–11) earlier operations. Osteomyelitis was estimated to be healed when the enclosed systemic antibiotic treatment and clinical controls were carried out and the patient didn't have symptoms of a persisting disease. The average postoperative follow up was 7,8 (3,0–59,0) months. Fifteen (75%) of the patients healed. One patient run out of controls, but was symptom free during his last visit. In four cases we had to remove the bioactive glass because of continuous secretion. In three cases the debridement was incomplete and one had a poor soft tissue cover and a candida infection. Adjuvant systemic antibiotic treatment was prescribed postoperatively 7,3 (4–19) weeks. Bioactive glass is an effective void filling material in the treatment of osteomyelitis. Proper debridement and a soft tissue cover should be performed. Main reason for that the five patients did not heal is, that this procedure is new and we were looking for the right indications and techniques

Introduction. Polymicrobial infections are expected to complicate the treatment of bone and joint infections. Septic nonunions often occur after initial open fractures, which prophylactically receive broad-spectrum antibiotics. However, no data that describes frequencies of polymicrobial infections and pathogens evident in course of the treatment of septic nonunions is published. Therefore, this study aims at investigating the frequency and pathogen types in polymicrobial infections. Methods. Surgically treated Patients with long bone septic nonunion admitted between January 2010 and March 2018 were included in the study. Following parameters were examined: age, gender, American Society of Anesthesiologists (ASA) score, body mass index (BMI), and anatomical location of the infected nonunion. Microbiological culture data, polymerase-chain-reaction results of tissue samples, sonication, and joint fluid of the initial and follow-up revision surgeries were assessed. No exclusion criteria were determined. Results. The study encompassed 42 patients with a mean age of 53.9 ± 17.7 years (range, 23 – 93). Sixteen (38.1%) patients were female. In 46.3% of the patients open fractures led to septic nonunion. Twenty-six nonunions occurred at the tibia or fibula, 11 were localized at the femur, 2 at the humerus and 3 at the forearm. Only 2 patients were assessed as ASA type 1, while 26 were ASA type 2 and 12 patients ASA type 3. Mean number of performed surgeries was 6 ± 0.67 (range 2 – 21). In 6 patients (14.3%) polymicrobial infection were evident. A change of evidenced pathogens in course of the treatment occurred in 21 patients (50%). In 16 patients (38.1%) previously detected bacteria could be evidenced by microbial testing after further revision surgery. Staphylococcus aureus was most often evident (n=34, 30.6%), followed by Enterococcus species (n=25, 22.5%) and Staphylococcus epidermidis (n=18, 16.2%). Five Staphylococcus aureus were resistant to methicillin (MRSA). In patients without polymicrobial infection or further germ detection in course of the treatment 86.4% of the infections were due to Staphylococcus species. Patients with change of detected pathogens and polymicrobial infections suffered from more enterococci infections. Infections due to streptococci and gram-negative bacteria could only be evidenced in patients with polymicrobial infection and pathogen change in course of the treatment. Conclusion. The observed difference of microbiological patterns in septic nonunion may help to facilitate adjuvant local and systemic antibiotic treatment in septic nonunion patients. Reasons for the observed difference of microbiological patterns and its influence on patient outcome have still to be elucidated

MRSA/MRSE infections appear to be increasing in prevalence and virulence. Prevalence has increased from 2.4% of all infected TJAs in 1975 to 37% in 2006. In addition work from several centers has shown that cure rates for these infections are far below that of nonresistant organisms. In a recent study from our institution 50 consecutive cases of MRSA/MRSE were treated with two-stage exchange with a Prostalac spacer as the interval operation. Final reinfection rate was 18% which was far worse than the 4% failure reported from our center in MS staph species. This high failure rate is supported by work from other centers. Clearly with the increasing prevalence and virulence of MRSA/MRSE new strategies are needed. The rest of this talk will focus on 2 different strategies: prevention and treatment. Prevention strategies can either target carriers or all patients. In a study by Kim et al. carriers were targeted and they reported a 50% reduction in surgical site infections. At our institution a recent program was implemented where all surgical patients were targeted. Results from this will be presented. While prevention strategies seem quite hopeful new treatment options have to be looked at. Traditionally vancomycin has been the mainstay of local and systemic treatment. Other options currently being explored include such agents as fusidic acid, daptomycin and liniazid. Research is looking at the effectiveness of these agents both locally and systemically. MRSA/MRSE infections are becoming increasingly difficult to treat. New strategies for combatting these will include both new prevention and treatment strategies as outlined in this talk

Heterotopic ossification (HO) is the formation of bone at extra-skeletal sites. Genetic diseases, traumatic injuries, or severe burns can induce this pathological condition and can lead to severe immobility. While the mechanisms by which the bony lesions arise are not completely understood, intense inflammation associated with musculoskeletal injury and/or highly invasive orthopaedic surgery is thought to induce HO. The incidence of HO has been reported between 3% and 90% following total hip arthroplasty. While the vast majority of these cases are asymptomatic, some patients will present decreased range of motion and painful swelling around the affected joints leading to severe immobility. In severe cases, ectopic bone formation may be involved in implant failure, leading to costly and painful revision surgery. The effects of surgical-related intraoperative risk factors for the formation of HO can also play a role. Prophylactic radiation therapy, and anti-inflammatory and biphosphonates agents have shown some promise in preventing HO, but their effects are mild to moderate at best and can be complicated with adverse effects. Irradiation around surgery could decrease the incidence of HO. However, high costs and the risk of soft tissue sarcoma inhibit the use of irradiation. Increased trials have demonstrated that nonsteroidal anti-inflammatory drugs (NSAID) are effective for the prevention of HO. However, the risk of gastrointestinal side effects caused by NSAID has drawn the attention of surgeons. The effect of the selective COX-2 inhibitor, celecoxib, is associated with a significant reduction in the incidence of HO in patients undergoing THA. Bone morphogenetic proteins (BMP) such as BMP2 identified another novel druggable target, i.e., the remote application of apyrase (ATP hydrolyzing agent) in the burn site decreased HO formation and mitigated functional impairment later. The question is if apyrase can be safely administered through other, such as systematical, routes. While the systemic treatments have shown general efficacy and are used clinically, there may be great benefit obtained from more localised treatment or from more targeted inhibitors of osteogenesis or chondrogenesis. In the surgical setting, prophylaxis for HO is regularly indicated due to the considerable risk of functional impairment. Heterotopic ossification is a well-known complication of total hip arthroplasty, especially when the direct lateral approach is used. Possible intraoperative risks are the size of incision, approach, duration of surgery and gender that can be associated with higher rates of HO or increase of the severity of HO. Like inflammation and tissue damage/ischemia are likely to be the key in the formation of HO, kindness to the soft tissues, tissue preserving surgery, pulse lavage to remove bone inducing factors and avoiding damage to all tissues should be erased as a comorbidity. Incision length, tissue dissection and subsequent localised trauma and ischemia, blood loss, anesthetic type and length of surgery may all contribute to the local inflammatory response. Data suggest that the surgeon may control the extent and nature of HO formation by limiting the incision length and if possible the length of the operation. Currently resection of HO is generally suggested after complete maturation (between 14–18 months), since earlier intervention is thought to predispose to recurrence. Reliable indicators of maturation of HO are diminishing activity on serial bone scans and/or decreasing levels of alkaline phosphatase. Although usually asymptomatic, heterotopic bone formation can cause major disability consisting of pain and a decreased range of motion in up to 7% of patients undergoing THA. Patients benefit from early resection of the heterotopic ossification with a proper and reliable postoperative strategy to prevent recurrence of HO with clinical implications

Periprosthetic infection remains a clinical challenge that may lead to revision surgeries, increased spending, disability, and mortality. The cost for treating hip and knee total joint infections is anticipated to be $1.62 billion by 2020. There is a need for implant surface modifications that simultaneously resist bacterial biofilm formation and adhesion, while promoting periprosthetic bone formation and osseointegration. In vitro research has shown that nanotextured titanium promotes osteoblast differentiation, and upregulates metabolic markers of osteoblast activity and osteoblast proliferation. In vivo rat studies confirmed increased bone-implant contact area, enhanced de novo bone formation on and adjacent to the implant, and higher pull-out forces compared to non-textured titanium. The authors have advanced a benign electrochemical anodization process based on ammonium fluoride that creates a nanotube surface in as little as 10 minutes (Fig. 1), which can also integrate antibacterial nanosilver (Fig. 2). The work reported here summarizes in vitro post-inoculation and in vivo post-implantation studies, showing inherent inhibition of methicillin-resistant Staphylococcus aureus (MRSA) by titanium surfaces with nanotubes (TiNT), nanotubes with nanosilver (TiNT+Ag), plain (Ti), and thermal plasma sprayed (TPS) titanium. Ti6Al4V was the base material for all surfaces. In vitro studies evaluated Ti, TPS, four TiNT groups with varying nanotube diameters (60nm, 80nm, 110nm, 150nm), and TiNT+Ag. After seeding with MRSA (10. 5. , 10. 6. , and 10. 8. CFU/mL), the 110nm diameter nanotubes showed MRSA inhibition up to three-orders of magnitude lower than the Ti and TPS surfaces at 2, 6, and 48 hours. Following on the in vitro results, New Zealand White rabbits underwent a bilateral implantation of intramedullary tibial implants of the four material groups (4 mm outside diameter; 110nm NT diameter on TiNT and TiNT+Ag implants). One intramedullary canal was inoculated with clinically-derived MRSA (10. 5. CFU in broth) at the time of implantation; one canal had only culture media introduced (control). At a 2-week endpoint, limbs were harvested for analysis, including implant sonication with sonicant bacterial cultured, histology, and microcomputed chromatography. In the sonicant analysis cohort, TPS showed the lowest average MRSA count, while TiNT and TiNT+Ag were the highest. There was one sample each of TPS, TiNT and TiNT+Ag that showed no MRSA. After an additional 24-hour implant incubation, the TiNT and TiNT+Ag samples had no bacteria, but the TPS grew bacteria; therefore, the authors hypothesize that MRSA more readily releases from the TiNT and TiNT+Ag implants during sonication, indicating weaker biofilm adhesion and development. Histologic analysis is currently underway. In a therapeutic experiment, rabbits underwent bilateral implantation, followed by 1 week of infection development, and then 1 week of vancomycin treatment. At the endpoint, implants were sonicated and bacteria was quantified from the sonicant. TiNT showed viable MRSA at only 30% that of TPS-coated levels, while TiNT+Ag implants showed viable MRSA at only 5% that of TPS-coated levels (Fig. 3). These early results indicate that the TiNT and TiNT+Ag surfaces have some inherent antibacterial activity against MRSA, which may increase the efficacy of systemic antibiotic treatments in the setting of periprosthetic joint infections

Introduction. Fungi are a rare and devastating cause of Periprosthetic Joint Infection (PJI). Diagnosis and treatment is a challenge as there are currently no specific guidelines. A recently published review identified 75 case reports of fungal PJI. Aim. The aim is to describe our experience of treating fungal PJI since 2011 within the Bone Infection Unit at our institution. Methods. A retrospective observational study including all patients who have received systemic or local antifungal treatment for PJI. Data was collected from electronic patient notes and databases. Results: We identified 10 patients who were treated for fungal PJI between May 2011 and March 2017. Demographics: Of the 10 patients, 7 were female and 3 were male. The mean age was 68 with a range of 19 to 87. The types of prosthesis infected were total knee (n=4), proximal femoral (n=2), total hip (n=1), distal femoral (n=1), total shoulder (n=1) and distal humoral (n=1) replacements. Organisms requiring treatment were all Candida species, including; C. albicans (n=3), C. parapsilosis (n=3), C. dublinensis (n=2), C. orthopsilosis (n=1) and C. glabrata (n=1). Treatment. Of the 10 patients, 8 had a 2-stage revision and 2 had single stage revision surgery. Local antifungal delivery using cement spacers loaded with voriconazole (300mg per 40g of bone cement), were used in all of the 5 cases where the fungi were identified prior to revision surgery. Initial systemic antifungal treatment continued for a mean duration of 2.6 months (range 0.9 to 8.4), and included caspofungin (n=4), fluconazole (n=6) and voriconazole (n=1). Of the 6 patients initially treated with azole antifungals, 3 patients required a change of antifungal treatment due to raised liver function tests. Clinical outcome. Outcome was established by the absence or presence of clinical signs of infection at a mean follow-up of 13.2 months (range 1 to 29). Of the 8 patients who had a 2-stage revision, 5 had a successful outcome, 2 were awaiting follow up to assess outcome and 1 was unsuccessful (required amputation). Of the patients who had a single stage revision, 1 was successful and there was 1 patient death (due to pulmonary embolism). Conclusion. Our case series supports current evidence supporting a two-stage revision strategy for fungal PJI. In this series caspofungin was better tolerated than azole antifungals

Bone metastases are the most common cause of cancer-related pain and often lead to other complications such as pathological fractures and spinal cord compression. Bisphosphonates (BP) are a class of potent anti-resorptive agents commonly prescribed to retard osteoporosis progression. Interestingly, BP may have indirect anti-tumour properties through negative effects on macrophages, osteoclasts, endothelial cells and their ability to suppress matrix metalloproteinase (MMP) activity. Currently, the use of bisphosphonates for cancer therapy is generally restricted to high dose systemic delivery. The purpose of this study was to investigate the effects of direct local delivery of Zoledronate at the metastatic site in a mouse model of breast cancer metastasis to bone. Seven days following intra-tibial inoculation with MDA-MB-231 (N = 1× 105) breast cancer cells in athymic mice, the experimental group (N = 11) was treated by direct infusion of 2µg of Zoledronate into the tibial lesion (three times/week for three weeks) and compared to vehicle-treated mice (N = 5). The formation of bone metastases and growth of the lesions were followed up by weekly bioluminescence imaging. In a subsequent experiment, a comparison of the effects of local versus systemic delivery of Zoledronate on the formation of osteolytic bone metastases was carried in athymic mice (N = 15). Seven days following intra-tibial inoculation with MDA-MB-231 breast cancer cells, the systemic group (N = 5) was treated with Zoledronate (0.025mg/kg) once per week for four weeks and compared to systemic delivery of vehicle (N = 4). Following treatment, the mice were sacrificed, and micro-CT images of the right tibia were obtained. Bone volume to tissue volume ratio (BV/TV%) was determined using µ-CT biomarkers. The first experiment showed a statistically significant increase in mean bone volume/tissue volume ratio% (BV/TV%) in the treated group (7.0±1.54%) as compared to the control group (3.8±0.48%) (P <0.001, 95%CI=1.9–4.3). This corresponded to a net increase of 84.21% in response to Zoledronate treatment. Comparison between the local and systemic effects of Zoledronate also revealed a significant increase in the BV/TV% in the locally treated group (6.69±0.62%) when compared to the cohort administered systemic bisphosphonate treatment (4.03±0.44%) (P<0.001, 95%CI=1.24–3.20), corresponding to a net increase of 66.0%. These preliminary results suggest that high dose sustained release of Zoledronate can lead to a significant inhibition of tumor-induced osteolysis. Moreover, comparison between local and systemic delivery revealed that the effect of local bisphosphonate administration exceeds the benefits of systemic delivery in terms of osteolysis inhibition. Lastly, the noted effects of Zoledronate local delivery triggers the need for further assessment of its anti-tumour activity

There is currently no consensus on the use of suppressive antibiotic therapy (SAT) in prosthetic joint infections (PJI) (1). We describe herein the experience of a French Reference Centre for Complex Osteo-Articular Infections on use of oral cyclines (doxycline and minocycline) for SAT. A retrospective analysis was performed on consecutive patients with PJI who received oral cyclines (doxycycline or minocycline) for SAT between January 2006 and June 2014. All patients had surgical management, followed by systemic antibiotic treatment and SAT instauration thereafter. Remission was defined as an asymptomatic patient with a functioning prosthesis. Seventy-nine patients with a mean age of 63.8 ± 16.8 years were included. Sixteen patients (20%) had neoplasia, 9 (11%) diabetes mellitus, 10 (13%) rheumatoid arthritis, and 6 patients (8%) were receiving corticosteroids or chemotherapy. There were 37 knee (47%), 36 hip (46%), 4 elbow (5%), and 2 shoulder (3%) infections, with a mean delay from implantation of 7.37 ± 6.94 months (range 1–27). Surgical management consisted in debridement and implant retention for 60 patients (76%), or in implant exchange for 19 patients (24%). Main pathogens were coagulase-negative staphylococci (37%) and Staphylococcus aureus (41%); 23 patients had polymicrobial infection (29%). The most frequent initial antibiotic regimens debuted before SAT were rifampicin combinations (70%). Mean duration of curative antibiotic therapy was 103 ± 75 days. Indications of SAT were (i) patients unsuitable for or refusing further surgery (n=23), suboptimal (ii) surgery (n=26) or (iii) curative antibiotic therapy (n=11), (iv) complex orthopaedic surgery (n=11), and (v) immunosuppressive status (n=8). Seventy-three patients received doxycycline and 6 patients received minocycline as SAT (n=48). Mean SAT duration was 625± 536 days (range 30–2900), with a mean follow-up of 765 ± 572 days. Adverse events were reported in 13 patients (16%), leading to SAT discontinuation in 5 (6%). During follow-up, 59 patients were considered in remission (75%), and 20 failed including 13 relapses (16%) and 7 reinfections (9%). Among failure patients, 10 pathogens resistant to doxy/minocycline were identified, including 5 with acquisition of cycline resistance. In our study, SAT with cyclines is associated to a 75% remission rate, with an acceptable tolerability. Further studies are warranted to determine ideal regimens and optimal duration of SAT. We would like to thank Dron Hospital and Lille University Hospital medical teams. The authors declare that there are no conflicts of interest

Open fractures are common, and infection a frequent complication. There is still uncertainty regarding the urgency of initial treatment. The majority of animal studies indicate that early irrigation and debridement reduces infection; unfortunately, these studies often do not involve antibiotics. Clinical studies indicate that the timing of initial debridement does not affect the infection rate. These studies are observational and fraught with confounding variables. The purpose of this study was to control for these variables using an animal model incorporating both systemic antibiotics and surgical treatment. This study used a segmental defect rat femur model contaminated with Staphylococcus aureus and treated with a 3 day course of systemic cefazolin (5 mg/Kg 12 hourly) and surgical treatments, both of which were initiated independently at 2, 6 and 24 hour time points. After 14 days bone and hardware was harvested for separate microbiological analysis. These results show that the earlier systemic antibiotic treatment or surgery is initiated. When antibiotics are started at 2 hours, delaying surgical treatment from 2 to 6 hours significantly increases infection (p=0.047). However, delaying surgery to 24 hours increases infection, but not significantly (p=0.054). The timing of antibiotics had a more significant effect on the proportion of positive samples than earlier surgery. At the 2 and 6 hour treatments, the p value was 0.004 and for the 6 and 24 timings it was 0.003. Surgery and antibiotics at 2 hours completely eradicates the bacteria, but surgical delay for 6 hours appears to allow the bacteria to form non-susceptible colonies. Delaying antibiotics to 6 or 24 hours had a profound detrimental effect on the infection rate regardless of timing of surgery. These findings are consistent with the concept that bacteria progress from a vulnerable planktonic form to a treatment-resistant biofilm

The treatment of chronic osteomyelitis requires both appropriate surgical and antibiotic management. Prolonged intravenous antibiotic therapy followed by oral therapy is widely utilised. Despite this, the long-term recurrence rate is approximately 25%. The aim of this cohort study was to examine the effectiveness of marginal surgical resection in combination with local application of antibiotics (Collatamp G - gentamicin in a collagen fleece). Post-operatively this was followed by a short course of intravenous antibiotics, then oral antibiotics, to 6 weeks in total. A cohort of 50 patients from a 10-year period, 2000 to 2010, with chronic osteomyelitis was identified. Most were male (n= 35, 70%) and the average age is 40.9 years (SD 15.9). The mean follow-up duration was 3.2 years (SD 1.8). The average length of admission was 9.8 days (SD 11.4). 6 patients (12%) suffered recurrence of infection requiring further treatment. We used the Cierny and Mader classification to stratify the patients further. There were 24 (48%) ‘A’ hosts and 26 (52%) ‘B’ hosts. ‘A’ hosts had a shorter duration of admission (7.1 days) than ‘B’ hosts (12.3 days). There was no significant difference between recurrence rates of ‘A’ and ‘B’ hosts. The available pre-operative C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) levels did not predict disease recurrence. Overall, the disease-free probability for this cohort was 0.80. A similar cohort treated with prolonged systemic and oral antibiotics reported by Simpson and colleagues (JBJS Br 2001) had a disease-free probability at 0.68. Local administration of gentamicin in a collagen fleece leads to improved disease-free probability when compared with prolonged systemic antibiotic treatment. We believe this is a useful component in the management of chronic osteomyelitis

Introduction. Open fractures are common, and infection a frequent complication. There is still uncertainty regarding the urgency of initial treatment. The majority of animal studies indicate that early irrigation and debridement reduces infection; unfortunately, these studies often do not involve antibiotics. Clinical studies indicate that the timing of initial debridement does not affect the infection rate. These studies are observational and fraught with confounding variables. The purpose of this study was to control for these variables using an animal model incorporating both systemic antibiotics and surgical treatment. Method. This study used a segmental defect rat femur model contaminated with Staphylococcus aureus and treated with a 3 day course of systemic cefazolin (5 mg/Kg 12 hourly) and surgical treatments, both of which were initiated independently at 2, 6 and 24 hour time points. After 14 days bone and hardware was harvested for separate microbiological analysis. Results. These results show that the earlier systemic antibiotic treatment or surgery is initiated. When antibiotics are started at 2 hours, delaying surgical treatment from 2 to 6 hours significantly increases infection (p=0.047). However, delaying surgery to 24 hours increases infection, but not significantly (p=0.054). The timing of antibiotics had a more significant effect on the proportion of positive samples than earlier surgery. At the 2 and 6 hour treatments, the p value was 0.004 and for the 6 and 24 timings it was 0.003. Conclusion. Surgery and antibiotics at 2 hours completely eradicates the bacteria, but surgical delay for 6 hours appears to allow the bacteria to form non-susceptible colonies. Delaying antibiotics to 6 or 24 hours had a profound detrimental effect on the infection rate regardless of timing of surgery. These findings are consistent with the concept that bacteria progress from a vulnerable planktonic form to a treatment-resistant biofilm

Aims

Calcium sulphate (CaSO₄) is a resorbable material that can be used simultaneously as filler of a dead space and as a carrier for the local application of antibiotics. Our aim was to describe the systemic exposure and the wound fluid concentrations of vancomycin in patients treated with vancomycin-loaded CaSO₄ as an adjunct to the routine therapy of bone and joint infections.